WO2023250116A1 - Modification de vert d'indocyanine (icg) pour le traitement du cancer du foie - Google Patents

Modification de vert d'indocyanine (icg) pour le traitement du cancer du foie Download PDF

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WO2023250116A1
WO2023250116A1 PCT/US2023/026034 US2023026034W WO2023250116A1 WO 2023250116 A1 WO2023250116 A1 WO 2023250116A1 US 2023026034 W US2023026034 W US 2023026034W WO 2023250116 A1 WO2023250116 A1 WO 2023250116A1
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optionally substituted
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Khashayar VAKILI
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The Children's Medical Center Corporation
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/041—Heterocyclic compounds
    • A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K51/0446—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0497—Organic compounds conjugates with a carrier being an organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/002—Heterocyclic compounds
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
    • C09B23/00—Methine or polymethine dyes, e.g. cyanine dyes
    • C09B23/02—Methine or polymethine dyes, e.g. cyanine dyes the polymethine chain containing an odd number of >CH- or >C[alkyl]- groups
    • C09B23/08—Methine or polymethine dyes, e.g. cyanine dyes the polymethine chain containing an odd number of >CH- or >C[alkyl]- groups more than three >CH- groups, e.g. polycarbocyanines
    • C09B23/086—Methine or polymethine dyes, e.g. cyanine dyes the polymethine chain containing an odd number of >CH- or >C[alkyl]- groups more than three >CH- groups, e.g. polycarbocyanines more than five >CH- groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

  • Radioisotope-containing compounds allow for the collection of information regarding the functioning of specific organs, biological processes, and the state or diagnosis of various disease states in a patient. Radioisotope-containing compounds can also be used for treating diseases, such as cancer. However, many radioisotope-containing compounds distribute broadly throughout the patient’s body, limiting the ability to collect localized information regarding disease states. Additionally, radioisotope-containing compounds that distribute broadly are limited in ability to treat localized disease processes, such as cancerous tumors. Accordingly, there is a need for radioisotope-containing compounds that are able to localize selectively to various tissue types, enhancing the ability to diagnose and treat diseases.
  • liver cancer is highly lethal due to the lack of effective therapeutic agents.
  • the most common types of liver cancer are epithelial in origin and include hepatocellular carcinoma (HCC), hepatoblastoma (HB), and fibrolamellar carcinoma (FLC).
  • HCC hepatocellular carcinoma
  • HB hepatoblastoma
  • FLC fibrolamellar carcinoma
  • OATP liverspecific organic acid solute transporters
  • Hepatocytes import ICG via the OATP transporters and excrete it into the biliary system via the MDR3 efflux transporter. Since tumor cells express the OATP transporters but do not have a biliary system, ICG accumulates in tumor tissue but is rapidly cleared from normal hepatocytes. This difference in the local pharmacokinetics of ICG is used intraoperatively to localize liver tumors. In clinical practice, ICG is administered intravenously 48-72 h prior to surgery; and tumor tissue, which accumulates ICG, is detected intraoperatively using near-infrared videography.
  • Hepatocyte-specific positron-emission tomography (PET) tracers have been developed by labeling indocyanine green (ICG) with radioisotopes (e.g., 18 F, ⁇ Cu, 67 Cu). These tracers demonstrate liver- specific uptake and suitable in vivo kinetics in wild-type mice, indicating that labeling ICG with radioisotopes does not significantly alter its ability to accumulate in hepatocytes. Given that ICG uptake by liver cancer has been validated preclinically and clinically, ICG may serve as a vector for the delivery of diagnostic and therapeutic radionuclides to liver cancer cells.
  • ICG indocyanine green
  • the present disclosure provides compounds of Formula I: and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, and prodrugs thereof, wherein the moieties and variables included in Formula I are as defined herein.
  • the provided compounds may be able to localize to liver cancer cells.
  • the present disclosure provides compounds of Formula I': and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, and prodrugs thereof, wherein the moieties and variables included in Formula T are as defined herein.
  • compositions comprising a provided compound and a pharmaceutically acceptable excipient.
  • kits comprising a provided compound or pharmaceutical composition and instructions for using the provided compound or pharmaceutical composition.
  • the present disclosure provides methods for diagnosing diseases in a subject in need thereof, the methods comprising administering to the subject an effective amount of a provided compound or pharmaceutical composition.
  • the present disclosure provides methods for treating diseases in a subject in need thereof, the methods comprising administering to the subject an effective amount of a provided compound or pharmaceutical composition.
  • the present disclosure provides methods for preventing diseases in a subject in need thereof, the methods comprising administering to the subject an effective amount of a provided compound or pharmaceutical composition.
  • the disease is cancer.
  • the present disclosure provides methods for inhibiting cell proliferation or promoting apoptosis in a subject in need thereof or in a cell, tissue, or biological sample, comprising administering to the subject or contacting the cell, tissue, or biological sample with an effective amount of a provided compound or pharmaceutical composition, wherein the cell, tissue, or biological sample is in vivo.
  • the present disclosure provides methods for inhibiting cell proliferation or promoting apoptosis in a subject in need thereof or in a cell, tissue, or biological sample, comprising administering to the subject or contacting the cell, tissue, or biological sample with an effective amount of a provided compound or pharmaceutical composition, wherein the cell, tissue, or biological sample is in vitro.
  • FIGs. 1A-1B show synthetic schemes for [ 18 F]SFB (FIG. 1A) and [ 18 F]FPyTFP (FIG. IB) and their reactions with ICG-amine.
  • FIGs. 2A-2D show HPEC traces of the reaction to form [ 18 F]SFB-ICG (C18-2).
  • FIG. 2A shows after 15 minutes.
  • FIG. 2B shows after 30 minutes.
  • FIG. 2C shows after 45 min.
  • FIG. 2D shows after 60 minutes.
  • FIGs. 3A-3D show HPLC traces of the unpurified [ 18 F]SFB-ICG Reaction (Polar-RP).
  • FIG. 3A shows [ 18 F]SFB prior to the reaction.
  • FIG. 3B shows [ 18 F]SFB and desired product after 30 minutes (hydrolysis).
  • FIG. 3C shows the desired product after 15 minutes.
  • FIG. 3D shows the desired product after 45 minutes.
  • the column utilized was Polar RP.
  • the mobile phase utilized Acetonitrile: Water (0.1% TFA) (20:80), Flow Rate: 1 mL/minute.
  • FIG. 4 shows HPLC traces of the reaction to form [ 18 F]SFB-ICG: Polar-RP, using the Semi-Prep Column: Polar RP-C18.
  • the mobile phase utilized Ethanol: PBS (lx) (10:90), with a flow rate of 5 mL/minute.
  • FIGs.5A-5B show HPLC traces of collected fractions of the reaction to form [ 18 F]SFB- ICG.
  • FIG. 5A shows the fractions collected between 7 and 8 minutes.
  • FIG. 5B shows the fractions collected between 9 and 10 minutes.
  • the analytical column used was Hydro RP-C18.
  • the mobile phase utilized Acetonitrile: Water (TFA 0.1%) (20:80) at a flow rate of 1 mL/minute.
  • FIGs. 6A-6B show reference standards of FBA and SFB upon using a Hydro RP-C18 column, Acetonitrile: Water (TFA 0.1%) (35:65) for the mobile phase with a flow through rate of 1 mL/minute.
  • FIG. 6A shows the reference standard for FBA;
  • FIG. 6B shows the reference standard for SFB.
  • FIGs. 7A-7D show HPLC traces of the reaction to form [ 18 F]SFB-ICG, unpurified and cold.
  • FIG. 7A shows after 5 minutes, with both FBA and SFB present, as well as possible product.
  • FIG. 7B shows after 30 minutes.
  • FIG. 7C shows after 15 minutes.
  • FIG. 7D shows after 45 minutes.
  • FIGs. 8A-8B show HPLC traces of the reaction to form [ 18 F]SFB-ICG.
  • FIG. 8A shows [ 18 F]SFB-ICG crude.
  • FIG. 8B shows [ 18 F]SFB-ICG semi-prep.
  • the total activity (EOS) was 17 mCi, 2 mCi/mL with a RCP of 38%.
  • FIGs. 9A-9B show HPLC traces of [ 18 F]SFB-ICG purifications with varying mobile phases.
  • FIG. 9A shows [ 18 F]SFB-ICG as a purified product from semi-prep column; Polar-RP- C18, with a mobile phase utilizing Ethanol: PBS (lx) (10:90). The flow through rate was 5 mL/minute.
  • FIG. 9B shows 18 F]SFB-ICG as a purified product from semi-prep column; Polar- RP-C18, with a mobile phase utilizing Ethanol: PBS (lx) (8:92), with a flow through rate of 5 mL/minute.
  • FIGs. 10A-10B show HPLC traces of [ 18 F]SFB-ICG (FIG. 10A) and [ 18 F]FBA (FIG. 10B). Both were purification products from the Semi-prep Column Hydro RP-C18, with a mobile phase utilizing Ethanol: Sodium Dihydrogen phosphate (25 mM) (10:90), with a flow through rate of 5mL/minute.
  • FIGs. 11A-11B show HPLC traces of [ 18 F]SFB-ICG stability at 1 hour, and 2 hours.
  • FIG. 11A shows [ 18 F]SFB-ICG at 1 hour, with a 95% RCP.
  • FIG. 11B shows [ 18 F]SFB-ICG at 2 hours, with a 96% RCP.
  • FIGs. 14A-14D show [ 18 F]ICG-A/B reaction-chromatograms.
  • FIG. 14A shows a table delineating the temperatures and their respective percent conversions.
  • FIG. 14B shows the radioactive traces at RT (15) and RT (30)+ 50 (15).
  • FIG. 14C shows the radioactive trace at RT 30+ 90 (15).
  • FIG. 14D shows the UV trace at RT (30) + 50 (30) + 90 (15).
  • FIGs. 17A-17D show PET/CT images of a representative wild type mouse.
  • FIGs. 18A-18B show Time Activity Curves for 18 F-SFB-ICG - All Organs of Interest.
  • FIG. 18A shows the activity concentration in Standardized Uptake Value (SUV).
  • FIG. 18B shows the activity uptake in percentage Injected Dose (%ID) for fully segmented organs. For large intestines and cecum, PET signal was not observed until the 4 hour time point, and thus these organs were not segmented (nor plotted) prior to that timepoint.
  • SUV Standardized Uptake Value
  • %ID percentage Injected Dose
  • FIGs. 19A-19B show Time Activity Curves for 18 F-SFB-ICG - Liver.
  • FIG. 19A shows the activity concentration in Standardized Uptake Value (SUV).
  • FIG. 19B shows the activity uptake in percentage Injected Dose (%ID) for fully segmented organ.
  • FIGs. 20A-20B show Time Activity Curves for 18 F-SFB-ICG - Gallbladder.
  • FIG. 20A shows the activity concentration in Standardized Uptake Value (SUV).
  • FIG. 20B shows the activity uptake in percentage Injected Dose (%ID) for fully segmented organ.
  • FIGs. 21A-21B show Time Activity Curves for 18F-SFB-ICG - Small Intestine.
  • FIG. 21A shows the activity concentration in Standardized Uptake Value (SUV).
  • FIG. 21B shows the activity uptake in percentage Injected Dose (%ID) for fully segmented organ.
  • FIGs. 22A-22B show Time Activity Curves for 18 F-SFB-ICG - Heart.
  • FIG. 22A shows the activity concentration in Standardized Uptake Value (SUV).
  • FIG. 22B shows the activity uptake in percentage Injected Dose (%ID) for fully segmented organ.
  • FIGs. 23A-23B show Time Activity Curves for 18 F-SFB-ICG - Spleen and Lungs.
  • FIG. 23A shows the activity concentration in Standardized Uptake Value (SUV) in the spleen.
  • FIG. 23B shows the activity concentration in Standardized Uptake Value (SUV) in the lungs.
  • FIGs. 24A-24B show Gamma Counting for 18 F-SFB-ICG - Whole Blood.
  • FIG. 24A shows the activity concentration in Standardized Uptake Value (SUV).
  • FIG. 24B shows the activity concentration (activity uptake) in percentage Injected Dose per gram (%ID/g) for whole blood.
  • FIGs. 25A-25D show 18 F-SFB-ICG distribution in group la mice at 0 (FIG. 25A), 15 (FIG. 25B), 30 (FIG. 25C), and 45 minutes (FIG. 25D) post-tracer injection (IV), as determined through whole body PET/CT at the specified time point.
  • FIGs. 26A-26D show 18 F-SFB-ICG distribution in group lb mice at 0 (FIG. 26A), 15 (FIG. 26B), 30 (FIG. 26C), and 45 minutes (FIG. 26D) post-tracer injection (IV), as determined through whole body PET/CT at the specified time point. By 5 minutes, the majority of the tracer is localized to the liver and by 45 minutes there is evidence of excretion of [ 18 F]ICG into the small intestine (arrow).
  • FIGs. 27A-27D show 18 F-SFB-ICG distribution in group la mice, 15 minute frame at 45 minutes post-tracer injection, as determined by whole body PET/CT at 45-60 minutes post tracerinjection (IV).
  • FIGs. 28A-28D show 18 F-SFB-ICG distribution in group lb mice, 15 minute frame at 45 minutes post-tracer injection, as determined by whole body PET/CT at 45-60 minutes post tracerinjection (IV).
  • FIGs. 29A-29D show 18 F-SFB-ICG distribution in group la mice, 15 minute frame at 4 hours post-tracer injection, as determined by whole body PET/CT at 4 hours post tracer-injection (IV). The most intense signal is present within the lumen of the intestines.
  • FIGs. 30A-30D show 18 F-SFB-ICG distribution in group lb mice, 15 minute frame at 4 hours post-tracer injection, as determined by whole body PET/CT at 4 hours post tracer-injection (IV). The most intense signal is present within the lumen of the intestines.
  • FIGs. 31A-31D show gross and microscopic ICG localization in FLC.
  • the patient was administered intravenous ICG 48 hours prior to surgery and the white fluorescent areas correspond to ICG accumulation.
  • FIG. 31A shows that T denotes tumor in the liver and NL denotes normal liver. There is clear demarcation between the tumor and normal liver.
  • FIG. 31B shows that a black arrow points to an exophytic portion of the tumor extending from the liver.
  • White arrow points to a lymph node outside of the liver and in the porta hepatis, demonstrating accumulation of ICG in metastatic tumor bed.
  • FIG. 31C shows a fluorescent microscopic image (@789 nm excitation wavelength) of unstained metastatic FLC section demonstrating fluorescence (white) within tumor cells.
  • FIG. 31D shows a control sample of processed tumor section in the absence of ICG demonstrating lack of fluorescence.
  • FIG. 32 shows in vivo fluorescence imaging following ICG administration. Implanted Huh7 cells demonstrate uptake at 0.5mg/kg dose. Other areas of high signal represents concentration within the intestinal lumen. Control mouse without tumor is shown on the left side.
  • Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and/or diastereomers.
  • the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer.
  • Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses.
  • HPLC high pressure liquid chromatography
  • a formula depicted herein includes compounds that do not include isotopically enriched atoms, and also includes compounds that include isotopically enriched atoms. Compounds that include isotopically enriched atoms may be useful as, for example, analytical tools, and/or probes in biological assays.
  • range When a range of values (“range”) is listed, it is intended to encompass each value and subrange within the range. A range is inclusive of the values at the two ends of the range unless otherwise provided.
  • C1-6 alkyl is intended to encompass, C1, C2, C3, C4, C5, C6, C1-6, Ci-5, CM, C1-3, C1-2, C2 6, C2-5, C2-4, C2-3, C3-6, C3-5, C3 4, C4 6, C4-5, and C 5 6 alkyl.
  • aliphatic refers to alkyl, alkenyl, alkynyl, and carbocyclic groups.
  • heteroaliphatic refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.
  • alkyl refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C1-20 alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“C1-12 alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“Ci-10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“Ci- 9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C1-8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1-7 alkyl”).
  • an alkyl group has 1 to 6 carbon atoms (“C1-6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“CIM alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“Ci alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-6 alkyl”).
  • C1-6 alkyl groups include methyl (Ci), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C5) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tert-amyl), and hexyl (Ce) (e.g., n-hexyl).
  • alkyl groups include n-heptyl (C7), n-octyl (C8), n-dodccyl (C12), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents (e.g., halogen, such as F).
  • substituents e.g., halogen, such as F
  • the alkyl group is an unsubstituted C1-12 alkyl (such as unsubstituted C1-6 alkyl, e.g., -CH3 (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted zi-butyl (zi-Bu), unsubstituted tert-butyl (tert-Bu or t- Bu), unsubstituted sec-butyl (sec-Bu or s-Bu), unsubstituted isobutyl (z-Bu)).
  • unsubstituted C1-6 alkyl e.g., -CH3 (Me), unsubstituted ethyl (E
  • the alkyl group is a substituted C1-12 alkyl (such as substituted C1-6 alkyl, e.g., - CH 2 F, -CHF 2 , -CF 3 , -CH2CH2F, -CH2CHF2, -CH2CF3, or benzyl (Bn)).
  • haloalkyl is a substituted alkyl group, wherein one or more of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo.
  • Perhaloalkyl is a subset of haloalkyl, and refers to an alkyl group wherein all of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo.
  • the haloalkyl moiety has 1 to 20 carbon atoms (“C1-20 haloalkyl”).
  • the haloalkyl moiety has 1 to 12 carbon atoms (“C1-12 haloalkyl”).
  • the haloalkyl moiety has 1 to 8 carbon atoms (“C1-8 haloalkyl”).
  • the haloalkyl moiety has 1 to 6 carbon atoms (“C1-6 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 4 carbon atoms (“C 1-4 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 3 carbon atoms (“C1-3 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 2 carbon atoms (“C1-2 haloalkyl”). In some embodiments, all of the haloalkyl hydrogen atoms are replaced with fluoro to provide a perfluoroalkyl group.
  • haloalkyl hydrogen atoms are replaced with chloro to provide a “perchloroalkyl” group.
  • haloalkyl groups include -CF3, - CF2CF3, -CF2CF2CF3, -CCI3, -CFCI2, -CF2CI, and the like.
  • heteroalkyl refers to an alkyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain.
  • a heteroalkyl group refers to a saturated group having from 1 to 20 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-20 alkyl” or “C1-20 heteroalkyl”).
  • a heteroalkyl group refers to a saturated group having from 1 to 12 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-12 alkyl”). In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 10 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1- 10 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-9 alkyl”).
  • a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCi-8 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-7 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-6 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC1-5 alkyl”).
  • a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and lor 2 heteroatoms within the parent chain (“hctcroC 1 4 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain (“heteroC1-3 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“heteroC1-2 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroCi alkyl”).
  • a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC2-6 alkyl”). Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an “unsubstituted heteroalkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents. In certain embodiments, the heteroalkyl group is an unsubstituted heteroCi-io alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroC1-10 alkyl.
  • alkenyl refers to a radical of a straight-chain or branched hydrocarbon group having from 1 to 20 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds) (“C1-20 alkenyl”).
  • an alkenyl group CH2.
  • an alkenyl group has 2 to 20 carbon atoms (“C2-20 alkenyl”).
  • an alkenyl group CH2.
  • an alkenyl group has 2 to 12 carbon atoms (“C2-12 alkenyl”).
  • an alkenyl group has 2 to 9 carbon atoms (“C2-9 alkenyl”).
  • an alkenyl group has 2 to 8 carbon atoms (“C2-8 alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C2-7 alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2-6 alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2-5 alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C2-4 alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2-3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C2 alkenyl”).
  • the one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl).
  • Examples of C2 4 alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like.
  • Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (Ce), and the like.
  • alkenyl examples include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents. In certain embodiments, the alkenyl group is an unsubstituted C2-10 alkenyl. In certain embodiments, the alkenyl group is a substituted C2-10 alkenyl.
  • heteroalkenyl refers to an alkenyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain.
  • heteroatom e.g., 1, 2, 3, or 4 heteroatoms
  • a heteroalkenyl group refers to a group having from 2 to 20 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-20 alkenyl” or “C2-20 heteroalkenyl”).
  • a heteroalkenyl group refers to a group having from 2 to 12 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-i2 alkenyl”).
  • a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-10 alkenyl”).
  • a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-9 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-8 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-7 alkenyl”).
  • a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-6 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-5 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and lor 2 heteroatoms within the parent chain (“hctcroC2 4 alkenyl”).
  • a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“heteroC2-3 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-6 alkenyl”). Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an “unsubstituted heteroalkenyl”) or substituted (a “substituted heteroalkenyl”) with one or more substituents. In certain embodiments, the heteroalkenyl group is an unsubstituted heteroC2-io alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroC2-io alkenyl.
  • alkynyl refers to a radical of a straight-chain or branched hydrocarbon group having from 1 to 20 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (“C1-20 alkynyl”).
  • an alkynyl group has 2 to 20 carbon atoms (“C2-20 alkynyl”).
  • an alkynyl group has 2 to 12 carbon atoms (“C2-12 alkynyl”).
  • an alkynyl group has 2 to 9 carbon atoms (“C2-9 alkynyl”).
  • an alkynyl group has 2 to 8 carbon atoms (“C2-8 alkynyl”). In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“C2-7 alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C2-6 alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C2-5 alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C2 4 alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C2-3 alkynyl”).
  • an alkynyl group has 2 carbon atoms (“C2 alkynyl”).
  • the one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1- butynyl).
  • Examples of C2-4 alkynyl groups include ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like.
  • Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkynyl groups as well as pentynyl (C5), hexynyl (Ce), and the like.
  • alkynyl examples include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents. In certain embodiments, the alkynyl group is an unsubstituted C2-10 alkynyl. In certain embodiments, the alkynyl group is a substituted C2-10 alkynyl.
  • heteroalkynyl refers to an alkynyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (/'. ⁇ ?., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain.
  • a heteroalkynyl group refers to a group having from 2 to 20 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-20 alkynyl” or “C2-20 heteralkynyl”).
  • a heteroalkynyl group refers to a group having from 2 to 12 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-i2 alkynyl”). In certain embodiments, a heteroalkynyl group refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-io alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-9 alkynyl”).
  • a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-8 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-7 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-6 alkynyl”).
  • a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-5 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and lor 2 heteroatoms within the parent chain (“hctcroC2 4 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroC2-3 alkynyl”).
  • a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-6 alkynyl”). Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an “unsubstituted heteroalkynyl”) or substituted (a “substituted heteroalkynyl”) with one or more substituents. In certain embodiments, the heteroalkynyl group is an unsubstituted heteroC2 10 alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC2-io alkynyl.
  • carbocyclyl refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms (“C3-14 carbocyclyl”) and zero heteroatoms in the non-aromatic ring system.
  • a carbocyclyl group has 3 to 10 ring carbon atoms (“C3-10 carbocyclyl”).
  • a carbocyclyl group has 3 to 8 ring carbon atoms (“C3-8 carbocyclyl”).
  • a carbocyclyl group has 3 to 7 ring carbon atoms (“C3-7 carbocyclyl”).
  • a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms (“C4-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C5-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10 carbocyclyl”). Exemplary C3-6 carbocyclyl groups include cyclopropyl
  • C3 cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce), and the like.
  • Exemplary C3-8 carbocyclyl groups include the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like.
  • Exemplary C3-10 carbocyclyl groups include the aforementioned C3-8 carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro- 1H- indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like.
  • the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and can be saturated or can contain one or more carbon-carbon double or triple bonds.
  • Carbocyclyl also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system.
  • each instance of a carbocyclyl group is independently unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents.
  • the carbocyclyl group is an unsubstituted C3-14 carbocyclyl.
  • the carbocyclyl group is a substituted C3-14 carbocyclyl. In certain embodiments, the carbocyclyl is substituted or unsubstituted, 3- to 8-membered, and monocyclic. In certain embodiments, the carbocyclyl is substituted or unsubstituted, 5- to 14-membered, and bicyclic. In certain embodiments, the carbocyclyl is substituted or unsubstituted, 6- to 14-membered, and tricyclic.
  • “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms (“C3-14 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms (“C3-10 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C3-8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms (“C4-6 cycloalkyl”).
  • a cycloalkyl group has 5 to 6 ring carbon atoms (“C5-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C5-10 cycloalkyl”). Examples of C5-6 cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3-6 cycloalkyl groups include the aforementioned C5-6 cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4).
  • C3-8 cycloalkyl groups include the aforementioned C3-6 cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (Cs).
  • each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents.
  • the cycloalkyl group is an unsubstituted C3-14 cycloalkyl.
  • the cycloalkyl group is a substituted C3-14 cycloalkyl.
  • heterocyclyl refers to a radical of a 3- to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3-14 membered heterocyclyl”).
  • heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • a heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”)), and can be saturated or can contain one or more carbon-carbon double or triple bonds.
  • Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings.
  • Heterocyclyl also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continues to designate the number of ring members in the heterocyclyl ring system.
  • each instance of heterocyclyl is independently unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents.
  • the heterocyclyl group is an unsubstituted 3-14 membered heterocyclyl.
  • the heterocyclyl group is a substituted 3-14 membered heterocyclyl.
  • the heterocyclyl is substituted or unsubstituted, 3- to 8-membered, monocyclic heterocyclyl, wherein
  • 1, 2, or 3 atoms in the heterocyclic ring system are independently oxygen, nitrogen, or sulfur, as valency permits.
  • the heterocyclyl is substituted or unsubstituted, 5- to 14-membered, bicyclic heterocyclyl, wherein 1, 2, 3, or 4 atoms in the heterocyclic ring system are independently oxygen, nitrogen, or sulfur, as valency permits.
  • the heterocyclyl is substituted or unsubstituted, 6- to 14-membered, tricyclic heterocyclyl, wherein 1,
  • 2, 3, or 4 atoms in the heterocyclic ring system are independently oxygen, nitrogen, or sulfur, as valency permits.
  • a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heterocyclyl”).
  • a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”).
  • a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”).
  • the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include aziridinyl, oxiranyl, and thiiranyl.
  • Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include azetidinyl, oxetanyl, and thietanyl.
  • Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2, 5-dione.
  • Exemplary 5- membered heterocyclyl groups containing 2 heteroatoms include dioxolanyl, oxathiolanyl and dithiolanyl.
  • Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include triazolinyl, oxadiazolinyl, and thiadiazolinyl.
  • Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl.
  • Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include piperazinyl, morpholinyl, dithianyl, and dioxanyl.
  • Exemplary 6-membered heterocyclyl groups containing 3 heteroatoms include triazinyl.
  • Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include azepanyl, oxepanyl and thiepanyl.
  • Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include azocanyl, oxecanyl and thiocanyl.
  • Exemplary bicyclic heterocyclyl groups include indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro- 1 ,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, lH-benzo[e] [ 1
  • aryl refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 7t electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“Ce-14 aryl”).
  • an aryl group has 6 ring carbon atoms (“Ce aryl”; e.g., phenyl).
  • an aryl group has 10 ring carbon atoms (“Cio aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl).
  • an aryl group has 14 ring carbon atoms (“Ci4 aryl”; e.g., anthracyl).
  • Aryl also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system.
  • each instance of an aryl group is independently unsubstituted (an “unsubstituted aryl,” e.g., unsubstituted phenyl (“Ph”)) or substituted (a “substituted aryl”) with one or more substituents.
  • the aryl group is an unsubstituted Ce-14 aryl- In certain embodiments, the aryl group is a substituted Ce-14 aryl.
  • Alkyl is a subset of “alkyl” and refers to an alkyl group substituted by an aryl group, wherein the point of attachment is on the alkyl moiety.
  • heteroaryl refers to a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 7t electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-14 membered heteroaryl”).
  • the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings.
  • Heteroaryl includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continues to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl/heteroaryl) ring system.
  • Polycyclic heteroaryl groups wherein one ring does not contain a heteroatom e.g., indolyl, quinolinyl, carbazolyl, and the like
  • the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).
  • the heteroaryl is substituted or unsubstituted, 5- or 6-membered, monocyclic heteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur.
  • the heteroaryl is substituted or unsubstituted, 9- or 10-membered, bicyclic heteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur.
  • a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”).
  • a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”).
  • a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”).
  • the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • each instance of a heteroaryl group is independently unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents.
  • the heteroaryl group is an unsubstituted 5-14 membered heteroaryl.
  • the heteroaryl group is a substituted 5-14 membered heteroaryl.
  • Exemplary 5-membered heteroaryl groups containing 1 heteroatom include pyrrolyl, furanyl, and thiophenyl.
  • Exemplary 5-membered heteroaryl groups containing 2 heteroatoms include imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.
  • Exemplary 5- membered heteroaryl groups containing 3 heteroatoms include triazolyl, oxadiazolyl, and thiadiazolyl.
  • Exemplary 5-membered heteroaryl groups containing 4 heteroatoms include tetrazolyl.
  • Exemplary 6-membered heteroaryl groups containing 1 heteroatom include pyridinyl.
  • Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include pyridazinyl, pyrimidinyl, and pyrazinyl.
  • Exemplary 6-membered heteroaryl groups containing 3 or 4 heteroatoms include triazinyl and tetrazinyl, respectively.
  • Exemplary 7-membered heteroaryl groups containing 1 heteroatom include azepinyl, oxepinyl, and thiepinyl.
  • Exemplary 5,6- bicyclic heteroaryl groups include indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl.
  • Exemplary 6,6-bicyclic heteroaryl groups include naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.
  • Exemplary tricyclic heteroaryl groups include phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl and phenazinyl.
  • Hetero aralkyl is a subset of “alkyl” and refers to an alkyl group substituted by a heteroaryl group, wherein the point of attachment is on the alkyl moiety.
  • unsaturated or “partially unsaturated” refers to a moiety that includes at least one double or triple bond.
  • saturated or “fully saturated” refers to a moiety that does not contain a double or triple bond, the moiety only contains single bonds.
  • alkylene is the divalent moiety of alkyl
  • alkenylene is the divalent moiety of alkenyl
  • alkynylene is the divalent moiety of alkynyl
  • heteroalkylene is the divalent moiety of heteroalkyl
  • heteroalkenylene is the divalent moiety of heteroalkenyl
  • heteroalkynylene is the divalent moiety of heteroalkynyl
  • carbocyclylene is the divalent moiety of carbocyclyl
  • heterocyclylene is the divalent moiety of heterocyclyl
  • arylene is the divalent moiety of aryl
  • heteroarylene is the divalent moiety of heteroaryl.
  • a group is optionally substituted unless expressly provided otherwise.
  • the term “optionally substituted” refers to being substituted or unsubstituted.
  • alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted.
  • Optionally substituted refers to a group which may be substituted or unsubstituted (e.g., “substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted” alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or “unsubstituted” heteroalkyl, “substituted” or “unsubstituted” heteroalkenyl, “substituted” or “unsubstituted” heteroalkynyl, “substituted” or “unsubstituted” carbocyclyl, “substituted” or “unsubstituted” heterocyclyl, “substituted” or “unsubstituted” aryl or “substituted” or “unsubstituted” heteroaryl group).
  • substituted means that at least one hydrogen present on a group is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.
  • a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position.
  • substituted is contemplated to include substitution with all permissible substituents of organic compounds, and includes any of the substituents described herein that results in the formation of a stable compound.
  • the present disclosure contemplates any and all such combinations in order to arrive at a stable compound.
  • heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety.
  • the disclosure is not intended to be limited in any manner by the exemplary substituents described herein.
  • each carbon atom of a moiety described herein is independently unsubstituted or substituted as valency permits (e.g., at valency 4).
  • a substituent on a carbon atom is a “carbon atom substituent.”
  • each nitrogen atom of a moiety described herein is independently unsubstituted or substituted as valency permits (e.g., at valency 3 or 5).
  • a substituent on a nitrogen atom is a “nitrogen atom substituent.”
  • each oxygen atom of a moiety described herein is independently unsubstituted or substituted as valency permits (e.g., at valency 2).
  • a substituent on an oxygen atom is a “oxygen atom substituent.”
  • each sulfur atom of a moiety described herein is independently unsubstituted or substituted as valency permits (e.g., at valency 2, 4, or 6).
  • a substituent on a sulfur atom is a “sulfur atom substituent.”
  • R aa is independently selected from the group consisting of Ci-io alkyl, Ci-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroCi-10 alkyl, heteroC2-ioalkenyl, heteroC2- loalkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-14 aryl, and 5-14 membered heteroaryl, or two R aa are joined to form 3-14 membered heterocyclyl or 5-14 membered heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd ; each instance of R bb is independently selected from the group consisting of hydrogen, - OH, -OR ⁇ , -N(R CC ) 2
  • X is a counterion
  • the carbon atom substituents are independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, -OR 2121 , -SR aa , -N(R bb )2, -CN, -SCN, or -NO2.
  • the carbon atom substituents are independently halogen, substituted (e.g., substituted with one or more halogen moieties) or unsubstituted Ci-6 alkyl, -OR ⁇ , -SR 2121 , -N(R bb )2, -CN, -SCN, or -NO2, wherein R aa is hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, Z-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl) when attached to an oxygen atom, or a sulfur protecting group (e.g., acetamidomethyl, Z-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphen
  • the molecular weight of a carbon atom substituent is lower than 250, lower than 200, lower than 150, lower than 100, or lower than 50 g/mol.
  • a carbon atom substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, nitrogen, and/or silicon atoms.
  • a carbon atom substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, and/or nitrogen atoms.
  • a carbon atom substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, and/or iodine atoms.
  • a carbon atom substituent consists of carbon, hydrogen, fluorine, and/or chlorine atoms.
  • halo or halogen refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).
  • hydroxyl refers to the group -OH.
  • thiol refers to the group -SH.
  • amino refers to the group -NH2.
  • substituted amino by extension, refers to a monosubstituted amino, a disubstituted amino, or a trisubstituted amino. In certain embodiments, the “substituted amino” is a monosubstituted amino or a disubstituted amino group.
  • trisubstituted amino refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with three groups, and includes groups selected from -N(R bb )3 and -N(R hh )3 + X , wherein R bb and X are as defined herein.
  • sulfonyl refers to a group selected from -SO2N(R bb )2, -SO2R aa , and - SO2OR aa , wherein R aa and R bb are as defined herein.
  • acyl groups include aldehydes (-CHO), carboxylic acids (-CO2H), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas.
  • Acyl substituents include, but are not limited to, any of the substituents described herein, that result in the formation of a stable moiety (e.g., aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, oxo, imino, thiooxo, cyano, isocyano, amino, azido, nitro, hydroxyl, thiol, halo, aliphaticamino, heteroaliphaticamino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy, alkyl
  • sil refers to the group -Si(R aa )s, wherein R aa is as defined herein.
  • phosphino refers to the group -P(R CC )3, wherein R cc is as defined herein.
  • An exemplary phosphino group is triphenylphosphine.
  • a nitrogen atom of a moiety described herein is a primary, secondary, tertiary, or quaternary nitrogen atom.
  • the nitrogen atom substituents are independently substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-6 alkyl or a nitrogen protecting group.
  • Nitrogen protecting groups may also be referred to as “amino protecting groups”. Nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
  • Nitrogen protecting groups such as carbamate groups include methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluorenylmethyl carbamate, 2,7-di-t-butyl-[9-(10,10-dioxo- 10,10,10,10-tetrahydrothioxanthyl)] methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate, l-(l-adamantyl)-l-methylethyl carbamate (Adpoc), 1,
  • Nitrogen protecting groups such as sulfonamide groups include p- toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6,-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4- methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6- dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6- sulfonamide (Pmc), methanesulfonamide (Ms), P
  • nitrogen protecting groups includephenothiazinyl-(10)-acyl derivative, N’-p- toluenesulfonylaminoacyl derivative, A’-phenylaminothioacyl derivative, N- benzoylphenylalanyl derivative, A-acetylmethionine derivative, 4,5-diphenyl-3-oxazolin-2- one, A-phthalimide, A-dithiasuccinimide (Dts), A-2,3-diphenylmaleimide, N-2,5- dimethylpyrrole, A-l ,1 ,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5- substituted l,3-dimethyl-l,3,5-triazacyclohexan-2-one, 5-substituted l,3-dibenzyl-l,3,5- triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4-pyr
  • a nitrogen protecting group is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts.
  • the oxygen atom substituents are independently substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-6 alkyl or an oxygen protecting group.
  • Oxygen protecting groups may also be referred to as “hydroxyl protecting groups”. Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
  • an oxygen protecting group is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, Z-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl.
  • each of the sulfur atom substituents is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl or a sulfur protecting group.
  • Sulfur protecting groups may also be referred to as “thiol protecting groups”. Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
  • the molecular weight of a substituent is lower than 250, lower than 200, lower than 150, lower than 100, or lower than 50 g/mol.
  • a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, nitrogen, and/or silicon atoms.
  • a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, and/or nitrogen atoms.
  • a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, and/or iodine atoms.
  • a substituent consists of carbon, hydrogen, fluorine, and/or chlorine atoms. In certain embodiments, a substituent comprises 0, 1, 2, or 3 hydrogen bond donors. In certain embodiments, a substituent comprises 0, 1, 2, or 3 hydrogen bond acceptors.
  • a “counterion” or “anionic counterion” is a negatively charged group associated with a positively charged group in order to maintain electronic neutrality.
  • An anionic counterion may be monovalent (i.e., including one formal negative charge).
  • An anionic counterion may also be multivalent (i.e., including more than one formal negative charge), such as divalent or trivalent.
  • Exemplary counterions include halide ions (e.g., F , Cl", Br , I”), NO 3 ", CIO4", OH", H2PO4 , HCOs", HSO4", sulfonate ions (e.g., methanesulfonate, trifluoromethanesulfonate, p- toluenesulfonate, benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate, naphthalene- 1 -sulfonic acid-5-sulfonate, ethan-1 -sulfonic acid-2-sulfonate, and the like), carboxylate ions (e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, and the like), BF 4 “, PF 4 ", PF 6 ", AsF 6 ", SbF 6 "
  • Exemplary counterions which may be multivalent include CO3 2 ”, HPO4 2- , PO4 3- , B4O? 2- , SO4 2- , S2O3 2- , carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like), and carboranes.
  • carboxylate anions e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like
  • carboranes e.g., tartrate, citrate, fumarate, maleate, malate, malonate,
  • LG is an art-understood term referring to an atomic or molecular fragment that departs with a pair of electrons in heterolytic bond cleavage, wherein the molecular fragment is an anion or neutral molecule.
  • a leaving group can be an atom or a group capable of being displaced by a nucleophile. See e.g., Smith, March Advanced Organic Chemistry 6th ed. (501-502).
  • Suitable leaving groups include, but are not limited to, halogen alkoxycarbonyloxy, aryloxycarbonyloxy, alkanesulfonyloxy, arenesulfonyloxy, alkyl-carbonyloxy (e.g., acetoxy), arylcarbonyloxy, aryloxy, methoxy, N,O- dimethylhydroxylamino, pixyl, and haloformates.
  • the leaving group is a brosylate, such as p-bromobenzenesulfonyloxy.
  • the leaving group is a nosylate, such as 2-nitrobenzenesulfonyloxy. In some embodiments, the leaving group is a sulfonate-containing group. In some embodiments, the leaving group is a tosylate group. In some embodiments, the leaving group is a phosphineoxide (e.g., formed during a Mitsunobu reaction) or an internal leaving group such as an epoxide or cyclic sulfate. Other non-limiting examples of leaving groups are water, ammonia, alcohols, ether moieties, thioether moieties, zinc halides, magnesium moieties, diazonium salts, and copper moieties.
  • phosphineoxide e.g., formed during a Mitsunobu reaction
  • Other non-limiting examples of leaving groups are water, ammonia, alcohols, ether moieties, thioether moieties, zinc halides, magnesium moieties, diazonium salts, and copper
  • the leaving group is optionally substituted amino. In some embodiments, the leaving group is trisubstituted amino (e.g., -N(R hh )3 + X , wherein R bb is as defined herein and X is a counterion).
  • salt refers to any and all salts, and encompasses pharmaceutically acceptable salts. Salts include ionic compounds that result from the neutralization reaction of an acid and a base. A salt is composed of one or more cations (positively charged ions) and one or more anions (negative ions) so that the salt is electrically neutral (without a net charge). Salts of the compounds of this disclosure include those derived from inorganic and organic acids and bases.
  • acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persul
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N + (C i > alkyl)4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.
  • pharmaceutically acceptable salt refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference.
  • Pharmaceutically acceptable salts of the compounds of this disclosure include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy- ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N + (C i > alkylJT salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.
  • solvate refers to forms of the compound, or a salt thereof, that are associated with a solvent, usually by a solvolysis reaction. This physical association may include hydrogen bonding.
  • Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like.
  • the compounds described herein may be prepared, e.g., in crystalline form, and may be solvated.
  • Suitable solvates include pharmaceutically acceptable solvates and further include both stoichiometric solvates and non- stoichiometric solvates. In certain instances, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of a crystalline solid.
  • “Solvate” encompasses both solutionphase and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates.
  • hydrate refers to a compound that is associated with water.
  • the number of the water molecules contained in a hydrate of a compound is in a definite ratio to the number of the compound molecules in the hydrate. Therefore, a hydrate of a compound may be represented, for example, by the general formula R x H2O, wherein R is the compound, and x is a number greater than 0.
  • a given compound may form more than one type of hydrate, including, e.g., monohydrates (x is 1), lower hydrates (x is a number greater than 0 and smaller than 1, e.g., hemihydrates (R O.5 H2O)), and polyhydrates (x is a number greater than 1, e.g., dihydrates (R-2 H2O) and hexahydrates (R-6 H2O)).
  • monohydrates x is 1
  • lower hydrates x is a number greater than 0 and smaller than 1, e.g., hemihydrates (R O.5 H2O)
  • polyhydrates x is a number greater than 1, e.g., dihydrates (R-2 H2O) and hexahydrates (R-6 H2O)
  • tautomers or “tautomeric” refers to two or more interconvertible compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valency (e.g., a single bond to a double bond, a triple bond to a single bond, or vice versa).
  • the exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Tautomerizations (/'. ⁇ ?., the reaction providing a tautomeric pair) may catalyzed by acid or base.
  • Exemplary tautomerizations include keto-to-enol, amide-to-imide, lactam-to-lactim, enamine-to- imine, and enamine-to-(a different enamine) tautomerizations.
  • stereoisomers that are not mirror images of one another are termed “diastereomers,” and those that are non-superimposable mirror images of each other are termed “enantiomers.”
  • enantiomers When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible.
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (/'. ⁇ ?., as (+) or (-)-isomers respectively).
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture.”
  • polymorph refers to a crystalline form of a compound (or a salt, hydrate, or solvate thereof). All polymorphs have the same elemental composition. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate. Various polymorphs of a compound can be prepared by crystallization under different conditions.
  • co-crystal refers to a crystalline structure comprising at least two different components (e.g., a compound and an acid), wherein each of the components is independently an atom, ion, or molecule. In certain embodiments, none of the components is a solvent. In certain embodiments, at least one of the components is a solvent.
  • a co-crystal of a compound and an acid is different from a salt formed from a compound and the acid. In the salt, a compound is complexed with the acid in a way that proton transfer (e.g., a complete proton transfer) from the acid to a compound easily occurs at room temperature.
  • a compound is complexed with the acid in a way that proton transfer from the acid to a herein does not easily occur at room temperature.
  • Co-crystals may be useful to improve the properties (e.g., solubility, stability, and ease of formulation) of a compound.
  • prodrugs refers to compounds that have cleavable groups and become by solvolysis or under physiological conditions the compounds described herein, which are pharmaceutically active in vivo. Such examples include choline ester derivatives and the like, N- alkylmorpholine esters and the like. Other derivatives of the compounds described herein have activity in both their acid and acid derivative forms, but in the acid sensitive form often offer advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, Bundgaard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985).
  • Prodrugs include, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides.
  • esters prepared by reaction of the parent acid with a suitable alcohol
  • amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine
  • acid anhydrides or mixed anhydrides.
  • a “subject” to which administration is contemplated refers to a human (z.e., male or female of any age group, e.g., pediatric subject (e.g., infant, child, or adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)) or non-human animal.
  • the non-human animal is a mammal (e.g., primate (e.g., cynomolgus monkey or rhesus monkey), commercially relevant mammal (e.g., cattle, pig, horse, sheep, goat, cat, or dog), or bird (e.g., commercially relevant bird, such as chicken, duck, goose, or turkey)).
  • primate e.g., cynomolgus monkey or rhesus monkey
  • commercially relevant mammal e.g., cattle, pig, horse, sheep, goat, cat, or dog
  • bird e.g., commercially relevant bird, such as
  • the non-human animal is a fish, reptile, or amphibian.
  • the non-human animal may be a male or female at any stage of development.
  • the non-human animal may be a transgenic animal or genetically engineered animal.
  • a “patient” refers to a human subject in need of diagnosis or treatment of a disease.
  • tissue sample refers to any sample including tissue samples (such as tissue sections and needle biopsies of a tissue); cell samples (e.g., cytological smears (such as Pap or blood smears) or samples of cells obtained by microdissection); samples of whole organisms (such as samples of yeasts or bacteria); or cell fractions, fragments or organelles (such as obtained by lysing cells and separating the components thereof by centrifugation or otherwise).
  • tissue samples such as tissue sections and needle biopsies of a tissue
  • cell samples e.g., cytological smears (such as Pap or blood smears) or samples of cells obtained by microdissection) or samples of cells obtained by microdissection
  • samples of whole organisms such as samples of yeasts or bacteria
  • cell fractions, fragments or organelles such as obtained by lysing cells and separating the components thereof by centrifugation or otherwise.
  • biological samples include blood, serum, urine, semen, fecal matter, cerebrospinal fluid, interstitial fluid, mucous, tears, sweat, pus, biopsied tissue (e.g., obtained by a surgical biopsy or needle biopsy), nipple aspirates, milk, vaginal fluid, saliva, swabs (such as buccal swabs), or any material containing biomolecules that is derived from a first biological sample.
  • administer refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein, or a pharmaceutical composition thereof, in or on a subject.
  • diagnosis refers to recognizing or identifying a disease described herein in a subject.
  • the subject has not previously been diagnosed with the disease.
  • the subject has previously been diagnosed with the disease.
  • the subject is at a higher risk of developing the disease or at a higher risk of regression of the disease than an average healthy member of a population of subjects.
  • diagnosis further comprises treatment or prevention.
  • treatment refers to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease described herein.
  • treatment may be administered after one or more signs or symptoms of the disease have developed or have been observed.
  • treatment may be administered in the absence of signs or symptoms of the disease.
  • treatment may be administered to a susceptible subject prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of exposure to a pathogen). Treatment may also be continued after symptoms have resolved, for example, to delay and/or prevent recurrence.
  • the treatment may be therapeutic treatment (not including prevention or prophylactic treatment).
  • prevent refers to a prophylactic treatment of a subject who is not and was not with a disease but is at risk of developing the disease or who was with a disease, is not with the disease, but is at risk of regression of the disease.
  • the subject is at a higher risk of developing the disease or at a higher risk of regression of the disease than an average healthy member of a population of subjects.
  • an “effective amount” of a compound refers to an amount sufficient to elicit the desired biological response.
  • An effective amount of a compound may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health of the subject.
  • the effective amount is a therapeutically effective amount.
  • the effective amount is a prophy tactically effective amount.
  • the effective amount is the amount of the compound in a single dose.
  • the effective amount is the combined amounts of the compound in multiple doses.
  • the desired dosage is delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks.
  • the desired dosage is delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations).
  • an effective amount of a compound for administration one or more times a day to a 70 kg adult human comprises about 0.0001 mg to about 3000 mg, about 0.0001 mg to about 2000 mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to about 1000 mg, about 0.01 mg to about 1000 mg, about 0.1 mg to about 1000 mg, about 1 mg to about 1000 mg, about 1 mg to about 100 mg, about 10 mg to about 1000 mg, or about 100 mg to about 1000 mg, of a compound per unit dosage form.
  • the compounds of the invention may be administered orally or parenterally at dosage levels sufficient to deliver from about 0.001 mg/kg to about 100 mg/kg, from about 0.01 mg/kg to about 50 mg/kg, preferably from about 0.1 mg/kg to about 40 mg/kg, preferably from about 0.5 mg/kg to about 30 mg/kg, from about 0.01 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 10 mg/kg, and more preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.
  • dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult.
  • the amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult.
  • a “therapeutically effective amount” of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more signs and/or symptoms associated with the condition, or to diagnose a condition.
  • the therapeutically effective amount is an amount that improves overall therapy, reduces or avoids symptoms, signs, or causes of the condition, and/or enhances the therapeutic efficacy of another therapeutic agent.
  • a therapeutically effective amount is an amount sufficient for detection in the subject.
  • a therapeutically effective amount is an amount sufficient for reducing the size of a tumor (e.g., reduction in size of a tumor by at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99%).
  • a therapeutically effective amount is an amount sufficient for treating a disease.
  • a therapeutically effective amount is an amount sufficient for reducing the size of a tumor and treating a disease.
  • a “proliferative disease” refers to a disease that occurs due to abnormal growth or extension by the multiplication of cells (Walker, Cambridge Dictionary of Biology, Cambridge University Press: Cambridge, UK, 1990).
  • a proliferative disease may be associated with: 1) the pathological proliferation of normally quiescent cells; 2) the pathological migration of cells from their normal location (e.g., metastasis of neoplastic cells); 3) the pathological expression of proteolytic enzymes such as the matrix metalloproteinases (e.g., collagenases, gelatinases, and elastases); or 4) the pathological angiogenesis as in proliferative retinopathy and tumor metastasis.
  • Exemplary proliferative diseases include cancers (z.e., “malignant neoplasms”) and benign neoplasms.
  • cancer refers to a class of diseases characterized by the development of abnormal cells that proliferate uncontrollably and have the ability to infiltrate and destroy normal body tissues. See, e.g., Stedman’s Medical Dictionary, 25th ed.; Hensyl ed.; Williams & Wilkins: Philadelphia, 1990.
  • the cancer may be a solid tumor.
  • the cancer may be a hematological malignancy.
  • Exemplary cancers include, but are not limited to, acoustic neuroma; adenocarcinoma; adrenal gland cancer; anal cancer; angiosarcoma (e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, hemangiosarcoma); appendix cancer; benign monoclonal gammopathy; biliary cancer (e.g., cholangiocarcinoma); bladder cancer; breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast); brain cancer (e.g., meningioma, glioblastomas, glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchus cancer; carcinoid tumor; cervical cancer (e.g., cervical adenocarcinoma); choriocar
  • Wilms tumor, renal cell carcinoma); liver cancer (e.g., hepatocellular cancer (HCC), malignant hepatoma, hepatic carcinoma); lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), nonsmall cell lung cancer (NSCLC), adenocarcinoma of the lung, squamous carcinoma of the lung); leiomyosarcoma (LMS); mastocytosis (e.g., systemic mastocytosis); muscle cancer; myelodysplastic syndrome (MDS); mesothelioma; myeloproliferative disorder (MPD) (e.g., polycythemia vera (PV), essential thrombocytosis (ET), agnogenic myeloid metaplasia (AMM) a.k.a.
  • HCC hepatocellular cancer
  • lung cancer e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), nonsmall cell lung cancer (NSCLC), a
  • myelofibrosis MF
  • chronic idiopathic myelofibrosis chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)
  • neuroblastoma e.g., neurofibromatosis (NF) type 1 or type 2, schwannomatosis
  • neuroendocrine cancer e.g., gastroenteropancreatic neuroendocrine tumor (GEP-NET), carcinoid tumor
  • osteosarcoma e.g., bone cancer
  • ovarian cancer e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma
  • papillary adenocarcinoma pancreatic cancer
  • pancreatic cancer e.g., pancreatic andenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), Islet cell tumors
  • penile cancer
  • neoplasm and “tumor” are used herein interchangeably and refer to an abnormal mass of tissue wherein the growth of the mass surpasses and is not coordinated with the growth of a normal tissue.
  • a neoplasm or tumor may be “benign” or “malignant,” depending on the following characteristics: degree of cellular differentiation (including morphology and functionality), rate of growth, local invasion, and metastasis.
  • a “benign neoplasm” is generally well differentiated, has characteristically slower growth than a malignant neoplasm, and remains localized to the site of origin.
  • a benign neoplasm does not have the capacity to infiltrate, invade, or metastasize to distant sites.
  • Exemplary benign neoplasms includelipoma, chondroma, adenomas, acrochordon, senile angiomas, seborrheic keratoses, lentigos, and sebaceous hyperplasias.
  • certain “benign” tumors may later give rise to malignant neoplasms, which may result from additional genetic changes in a subpopulation of the tumor’s neoplastic cells, and these tumors are referred to as “pre-malignant neoplasms.”
  • An exemplary pre-malignant neoplasm is a teratoma.
  • a “malignant neoplasm” is generally poorly differentiated (anaplasia) and has characteristically rapid growth accompanied by progressive infiltration, invasion, and destruction of the surrounding tissue. Furthermore, a malignant neoplasm generally has the capacity to metastasize to distant sites.
  • the term “metastasis,” “metastatic,” or “metastasize” refers to the spread or migration of cancerous cells from a primary or original tumor to another organ or tissue and is typically identifiable by the presence of a “secondary tumor” or “secondary cell mass” of the tissue type of the primary or original tumor and not of that of the organ or tissue in which the secondary (metastatic) tumor is located.
  • a prostate cancer that has migrated to bone is said to be metastasized prostate cancer and includes cancerous prostate cancer cells growing in bone tissue.
  • immunotherapy refers to a therapeutic agent that promotes the treatment of disease by inducing, enhancing, or suppressing an immune response.
  • Immunotherapies designed to elicit or amplify an immune response are classified as activation immunotherapies, while immunotherapies that reduce or suppress are classified as suppression immunotherapies.
  • Immunotherapies are typically, but not always, biotherapeutic agents. Numerous immunotherapies are used to treat cancer. These include, but are not limited to, monoclonal antibodies, adoptive cell transfer, cytokines, chemokines, vaccines, and small molecule inhibitors.
  • liver disease refers to damage to or a disease of the liver.
  • liver disease include intrahepatic cholestasis (e.g., alagille syndrome, biliary liver cirrhosis), fatty liver (e.g., alcoholic fatty liver, Reye’s syndrome), hepatic vein thrombosis, hepatolenticular degeneration (z.e., Wilson’s disease), hepatomegaly, liver abscess (e.g., amebic liver abscess), liver cirrhosis (e.g., alcoholic, biliary, and experimental liver cirrhosis), alcoholic liver diseases (e.g., fatty liver, hepatitis, cirrhosis), parasitic liver disease (e.g., hepatic echinococcosis, fascioliasis, amebic liver abscess), jaundice (e.g., hemolytic,
  • small molecule or “small molecule therapeutic” refers to molecules, whether naturally occurring or artificially created (e.g., via chemical synthesis) that have a relatively low molecular weight.
  • a small molecule is an organic compound (z.e., it contains carbon).
  • the small molecule may contain multiple carbon-carbon bonds, stereocenters, and other functional groups (e.g., amines, hydroxyl, carbonyls, and heterocyclic rings, etc.).
  • the molecular weight of a small molecule is not more than about 1,000 g/mol, not more than about 900 g/mol, not more than about 800 g/mol, not more than about 700 g/mol, not more than about 600 g/mol, not more than about 500 g/mol, not more than about 400 g/mol, not more than about 300 g/mol, not more than about 200 g/mol, or not more than about 100 g/mol.
  • the molecular weight of a small molecule is at least about 100 g/mol, at least about 200 g/mol, at least about 300 g/mol, at least about 400 g/mol, at least about 500 g/mol, at least about 600 g/mol, at least about 700 g/mol, at least about 800 g/mol, or at least about 900 g/mol, or at least about 1,000 g/mol. Combinations of the above ranges (e.g., at least about 200 g/mol and not more than about 500 g/mol) are also possible.
  • the small molecule is a therapeutically active agent such as a drug (e.g., a molecule approved by the U.S.
  • the small molecule may also be complexed with one or more metal atoms and/or metal ions.
  • the small molecule is also referred to as a “small organometallic molecule.”
  • Preferred small molecules are biologically active in that they produce a biological effect in animals, preferably mammals, more preferably humans. Small molecules include, but are not limited to, radionuclides and imaging agents.
  • the small molecule is a drug.
  • the drug is one that has already been deemed safe and effective for use in humans or animals by the appropriate governmental agency or regulatory body. For example, drugs approved for human use are listed by the FDA under 21 C.F.R.
  • therapeutic agent refers to any substance having therapeutic properties that produce a desired, usually beneficial, effect.
  • therapeutic agents may treat and/or ameliorate a disease.
  • Therapeutic agents, as disclosed herein, may be biologies or small molecule therapeutics, or combinations thereof.
  • isotopes refers to variants of a particular chemical element such that, while all isotopes of a given element share the same number of protons in each atom of the element, those isotopes differ in the number of neutrons.
  • radiationoisotope refers to an unstable isotope, the nucleus of which loses energy by emitting particles or rays (e.g., alpha particles, beta particles, and gamma rays) of ionizing radiation.
  • radioisotopes include, but are not limited to, n C, 18 F, 13 N, 15 O, ⁇ Cu, 67 Ga, 68 Ga, 75 Se, 81m Kr, 82 Rb, " m Tc, in In, 123 I, 125 I, 131 I, 133 Xe.
  • the term “radioactivity” or “radioactive decay” refers to the process by which a nucleus of an unstable isotope (e.g., 18 F) loses energy by emitting particles or rays (e.g., alpha particles, beta particles, and gamma rays) of ionizing radiation.
  • the term “specific activity” refers to the unit radioactivity of a material (e.g., a compound of Formula I, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or prodrug thereof). In certain embodiments, the term “specific activity” refers to the radioactivity of a material per micromole (pmol) of the material.
  • standardized uptake value refers to the ratio of activity per unit volume of a region of interest (e.g., a tissue) to the activity per unit whole body volume.
  • the term “standardized uptake value” is determined using positron emission tomography (PET) imaging.
  • PET positron emission tomography
  • time- activity curve refers to a curve of radioactivity plotted against time. In certain embodiments, the radioactivity is measured in a region of interest (e.g., a tissue).
  • linker refers to a bond or a divalent chemical moiety that is bonded to (z.e., that connects) two separate monovalent chemical moieties (e.g., N and R 1 in Formula I).
  • compounds e.g. compounds of Formula I, Formula I'
  • pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, and prodrugs thereof and pharmaceutical compositions and kits thereof.
  • the compounds provided herein are indocyanine green (ICG) derivatives and can be used to diagnose, treat, and/or prevent diseases in a subject.
  • methods of diagnosing, treating, and/or preventing a disease e.g. a proliferative disease
  • the compound or pharmaceutical composition may be administered as a monotherapy or in combination with another therapy, as described herein.
  • the present disclosure provides compounds of Formula I: and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, and prodrugs thereof, wherein:
  • L is a linker
  • the present disclosure provides compounds of Formula F: and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, and prodrugs thereof, wherein:
  • L is a linker
  • L is a linker.
  • L is a bond; substituted or unsubstituted alkylene; substituted or unsubstituted alkenylene; substituted or unsubstituted alkynylene; substituted or unsubstituted heteroalkylene; substituted or unsubstituted heteroalkenylene; substituted or unsubstituted heteroalkynylene; substituted or unsubstituted heterocyclylene; substituted or unsubstituted carbocyclylene; substituted or unsubstituted arylene; substituted or unsubstituted heteroarylene; peptidyl groups; dipeptidyl groups; polypeptidyl groups; or combination thereof.
  • L is substituted or unsubstituted alkylene. In certain embodiments, L is substituted alkylene. In certain embodiments, L is unsubstituted alkylene. In certain embodiments, L is alkylene substituted with an acyl group.
  • L is of formula In certain embodiments, L is of formula
  • each occurrence of Y 1 is independently C(R E1 )2, NR E2 , or -O-; and m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  • at least one occurrence of Y 1 is C(R E1 ) 2 .
  • at least one occurrence of Y 1 is CH2.
  • at least one occurrence of Y 1 is NR E2 .
  • at least one occurrence of Y 1 is NH.
  • at least one occurrence of Y 1 is oxygen.
  • At least one occurrence of Y 1 is CH2, R 1 is -N(R A )2 and contains at least one radioisotope, -OR A and contains at least one radioisotope, or -C(R A )3 and contains at least one radioisotope. In certain embodiments, at least one occurrence of Y 1 is CH2 and R 1 is - N(R A ) 2 and contains at least one radioisotope. In certain embodiments, at least one occurrence of Y 1 is CH2 and R 1 is -NHR A and contains at least one radioisotope. In certain embodiments, at least one occurrence of Y 1 is CH2 and R 1 is -OR A and contains at least one radioisotope. In certain embodiments, at least one occurrence of Y 1 is CH2 and R 1 is -C(R A )3 and contains at least one radioisotope.
  • m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is 3. In certain embodiments, m is 4. In certain embodiments, m is 5. In certain embodiments, m is 6. In certain embodiments, m is 7. In certain embodiments, m is 8. In certain embodiments, m is 9. In certain embodiments, m is 10. In certain embodiments, m is 5 and at least one occurrence of Y 1 is CH2. In certain embodiments, (Y ⁇ m is (CtDs.
  • (Y ⁇ m is (CtDs, R 1 is -N(R A )2 and contains at least one radioisotope, -OR A and contains at least one radioisotope, or -C(R A )3 and contains at least one radioisotope.
  • (Y ⁇ m is (CtDs and R 1 is -N(R A )2 and contains at least one radioisotope.
  • (Y ⁇ m is (CtDs and R 1 is -NHR A and contains at least one radioisotope.
  • (Y ⁇ m is (CtDs and R 1 is -OR A and contains at least one radioisotope.
  • (Y ⁇ m is (CtDs and R 1 is -C(R A )3 and contains at least one radioisotope.
  • At least one occurrence of R E1 is hydrogen. In certain embodiments, at least one occurrence of R E1 is halogen. In certain embodiments, at least one occurrence of R E1 is fluorine, chlorine, or bromine. In certain embodiments, at least one occurrence of R E1 is fluorine. In certain embodiments, at least one occurrence of R E1 is optionally substituted C1-12 alkyl. In certain embodiments, at least one occurrence of R E1 is optionally substituted C1-6 alkyl. In certain embodiments, at least one occurrence of R E1 is unsubstituted C1-6 alkyl. In certain embodiments, at least one occurrence of R E1 is substituted C1-6 alkyl.
  • R E1 is substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted tert-butyl, substituted or unsubstituted .sec-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted n-pentyl, substituted or unsubstituted 3-pentanyl, substituted or unsubstituted amyl, substituted or unsubstituted neopentyl, substituted or unsubstituted 3-methyl-2-butanyl, substituted or unsubstituted tert-amyl, or substituted or unsubstituted n-hcxyl.
  • At least one occurrence of R E1 is optionally substituted C2-6 alkenyl. In certain embodiments, at least one occurrence of R E1 is substituted or unsubstituted ethenyl, substituted or unsubstituted 1-propenyl, substituted or unsubstituted 2- propenyl, substituted or unsubstituted 1-butenyl, substituted or unsubstituted 2-butenyl, substituted or unsubstituted butadienyl, substituted or unsubstituted pentenyl, substituted or unsubstituted pentadienyl, or substituted or unsubstituted hexenyl.
  • At least one occurrence of R E1 is optionally substituted C2-6 alkynyl. In certain embodiments, at least one occurrence of R E1 is substituted or unsubstituted ethynyl, substituted or unsubstituted 1- propynyl, substituted or unsubstituted 2-propynyl, substituted or unsubstituted 1-butynyl, substituted or unsubstituted 2-butynyl, substituted or unsubstituted pentynyl, or substituted or unsubstituted hexynyl. In certain embodiments, at least one occurrence of R E1 is optionally substituted heteroC1-6 alkyl.
  • At least one occurrence of R E1 is optionally substituted heteroC1-6 alkenyl. In certain embodiments, at least one occurrence of R E1 is optionally substituted heteroC1-12 alkynyl. In certain embodiments, at least one occurrence of R E1 is optionally substituted heteroC1-6 alkynyl. In certain embodiments, at least one occurrence of R E1 is -CN, -OR A , -SR A , or -N(R A ) 2 .
  • At least one occurrence of R E2 is hydrogen. In certain embodiments, at least one occurrence of R E2 is optionally substituted C1-12 alkyl. In certain embodiments, at least one occurrence of R E2 is optionally substituted C1-6 alkyl. In certain embodiments, at least one occurrence of R E2 is unsubstituted C1-6 alkyl. In certain embodiments, at least one occurrence of R E2 is substituted C1-6 alkyl.
  • R E2 is substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted tert-butyl, substituted or unsubstituted secbutyl, substituted or unsubstituted isobutyl, substituted or unsubstituted n-pentyl, substituted or unsubstituted 3-pentanyl, substituted or unsubstituted amyl, substituted or unsubstituted neopentyl, substituted or unsubstituted 3-methyl-2-butanyl, substituted or unsubstituted tertamyl, or substituted or unsubstituted n-hcxyl.
  • At least one occurrence of R E2 is optionally substituted C2-6 alkenyl. In certain embodiments, at least one occurrence of R E2 is substituted or unsubstituted ethenyl, substituted or unsubstituted 1-propenyl, substituted or unsubstituted 2-propenyl, substituted or unsubstituted 1-butenyl, substituted or unsubstituted 2- butenyl, substituted or unsubstituted butadienyl, substituted or unsubstituted pentenyl, substituted or unsubstituted pentadienyl, or substituted or unsubstituted hexenyl.
  • At least one occurrence of R E2 is optionally substituted C2-6 alkynyl. In certain embodiments, at least one occurrence of R E2 is substituted or unsubstituted ethynyl, substituted or unsubstituted 1- propynyl, substituted or unsubstituted 2-propynyl, substituted or unsubstituted 1-butynyl, substituted or unsubstituted 2-butynyl, substituted or unsubstituted pentynyl, or substituted or unsubstituted hexynyl. In certain embodiments, at least one occurrence of R E2 is optionally substituted heteroC1-6 alkyl.
  • At least one occurrence of R E2 is optionally substituted heteroC1-6 alkenyl. In certain embodiments, at least one occurrence of R E2 is optionally substituted heteroC1-12 alkynyl. In certain embodiments, at least one occurrence of R E2 is optionally substituted heteroC1-6 alkynyl. In certain embodiments, at least one occurrence of R E2 is a nitrogen protecting group.
  • R 1 is a halogen radioisotope.
  • R 1 is a fluorine radioisotope (e.g., 18 F), a chlorine radioisotope, or a bromine radioisotope.
  • R 1 is a copper radioisotope (e.g., 64 Cu, 67 Cu).
  • R 1 is optionally substituted C1-12 alkyl and contains at least one radioisotope.
  • R 1 is optionally substituted C1-6 alkyl and contains at least one radioisotope.
  • R 1 is unsubstituted C1-6 alkyl and contains at least one radioisotope.
  • R 1 is substituted C1-6 alkyl and contains at least one radioisotope. In certain embodiments, R 1 is substituted or unsubstituted methyl and contains at least one radioisotope, substituted or unsubstituted ethyl and contains at least one radioisotope, substituted or unsubstituted n-propyl and contains at least one radioisotope, substituted or unsubstituted isopropyl and contains at least one radioisotope, substituted or unsubstituted n-butyl and contains at least one radioisotope, substituted or unsubstituted tert-butyl and contains at least one radioisotope, substituted or unsubstituted sec-butyl and contains at least one radioisotope, substituted or unsubstituted isobutyl and contains at least one radioisotope, substituted or unsubstituted n-pentyl and contains at least
  • R 1 is optionally substituted C2-12 alkenyl and contains at least one radioisotope. In certain embodiments, R 1 is optionally substituted C 2 -6 alkenyl and contains at least one radioisotope. In certain embodiments, R 1 is substituted or unsubstituted ethenyl and contains at least one radioisotope, substituted or unsubstituted 1-propenyl and contains at least one radioisotope, substituted or unsubstituted 2-propenyl and contains at least one radioisotope, substituted or unsubstituted 1-butenyl and contains at least one radioisotope, substituted or unsubstituted 2-butenyl and contains at least one radioisotope, substituted or unsubstituted butadienyl and contains at least one radioisotope, substituted or unsubstituted pentenyl and contains at least one radioisotope, substituted or unsubstituted pentenyl and
  • R 1 is optionally substituted C2-12 alkynyl and contains at least one radioisotope. In certain embodiments, R 1 is optionally substituted C 2 -6 alkynyl and contains at least one radioisotope. In certain embodiments, R 1 is substituted or unsubstituted ethynyl and contains at least one radioisotope, substituted or unsubstituted 1-propynyl and contains at least one radioisotope, substituted or unsubstituted 2-propynyl and contains at least one radioisotope, substituted or unsubstituted 1-butynyl and contains at least one radioisotope, substituted or unsubstituted 2-butynyl and contains at least one radioisotope, substituted or unsubstituted pentynyl and contains at least one radioisotope, or substituted or unsubstituted hexynyl and contains at least one radioisotope
  • R 1 is optionally substituted heteroCi 12 alkyl and contains at least one radioisotope. In certain embodiments, R 1 is optionally substituted heteroCi -6 alkyl and contains at least one radioisotope. In certain embodiments, R 1 is optionally substituted heteroCi -12 alkenyl and contains at least one radioisotope. In certain embodiments, R 1 is optionally substituted heteroC1-6 alkenyl and contains at least one radioisotope. In certain embodiments, R 1 is optionally substituted heteroCi -12 alkynyl and contains at least one radioisotope. In certain embodiments, R 1 is optionally substituted hclcroCi 6 alkynyl and contains at least one radioisotope.
  • R 1 is optionally substituted C3-14 cycloalkyl and contains at least one radioisotope. In certain embodiments, R 1 is optionally substituted 5-10 membered heterocyclyl and contains at least one radioisotope. In certain embodiments, R 1 is optionally substituted 6-14 membered aryl and contains at least one radioisotope. In certain embodiments, R 1 is optionally substituted 5-14 membered heteroaryl and contains at least one radioisotope.
  • R 1 is -N(R A )2 and contains at least one radioisotope, -OR A and contains at least one radioisotope, or -C(R A )3 and contains at least one radioisotope.
  • R 1 is -N(R A )2 and contains at least one radioisotope.
  • R 1 is -NHR A and contains at least one radioisotope.
  • R 1 is-OR A and contains at least one radioisotope.
  • R 1 is-C(R A )3 and contains at least one radioisotope.
  • R 1 is a halogen. In certain embodiments, R 1 is a fluorine, a chlorine, or a bromine. In certain embodiments, R 1 is optionally substituted C1-12 alkyl. In certain embodiments, R 1 is optionally substituted C1-6 alkyl. In certain embodiments, R 1 is unsubstituted C1-6 alkyl. In certain embodiments, R 1 is substituted C1-6 alkyl.
  • R 1 is substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n- butyl, substituted or unsubstituted tert-butyl, substituted or unsubstituted sec -butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted n-pentyl, substituted or unsubstituted 3- pentanyl, substituted or unsubstituted amyl, substituted or unsubstituted neopentyl, substituted or unsubstituted 3-methyl-2-butanyl, substituted or unsubstituted tert-amyl, or substituted or unsubstituted n-hcxyl.
  • R 1 is optionally substituted C2-12 alkenyl. In certain embodiments, R 1 is optionally substituted C2-6 alkenyl. In certain embodiments, R 1 is substituted or unsubstituted ethenyl, substituted or unsubstituted 1-propenyl, substituted or unsubstituted 2-propenyl, substituted or unsubstituted 1-butenyl, substituted or unsubstituted 2- butenyl, substituted or unsubstituted butadienyl, substituted or unsubstituted pentenyl, substituted or unsubstituted pentadienyl, or substituted or unsubstituted hexenyl.
  • R 1 is optionally substituted C2-12 alkynyl. In certain embodiments, R 1 is optionally substituted C2-6 alkynyl. In certain embodiments, R 1 is substituted or unsubstituted ethynyl, substituted or unsubstituted 1-propynyl, substituted or unsubstituted 2-propynyl, substituted or unsubstituted 1-butynyl, substituted or unsubstituted 2-butynyl, substituted or unsubstituted pentynyl, or substituted or unsubstituted hexynyl. In certain embodiments, R 1 is optionally substituted heteroC1-12 alkyl.
  • R 1 is optionally substituted heteroC1-6 alkyl. In certain embodiments, R 1 is optionally substituted heteroCi -12 alkenyl. In certain embodiments, R 1 is optionally substituted heteroCi -6 alkenyl. In certain embodiments, R 1 is optionally substituted heteroCi-i2 alkynyl. In certain embodiments, R 1 is optionally substituted heteroC1-6 alkynyl. In certain embodiments, R 1 is optionally substituted C3-14 cycloalkyl. In certain embodiments, R 1 is optionally substituted 5-10 membered heterocyclyl. In certain embodiments, R 1 is optionally substituted 6-14 membered aryl. In certain embodiments, R 1 is optionally substituted 5-14 membered heteroaryl.
  • each occurrence of R A is independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two occurrences of R A are joined together with their intervening atom to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring.
  • At least one occurrence of R A contains at least one radioisotope.
  • At least one occurrence of R A is hydrogen. In certain embodiments, at least one occurrence of R A is optionally substituted acyl. In certain embodiments, at least one occurrence of R A is optionally substituted C1-12 alkyl. In certain embodiments, at least one occurrence of R A is optionally substituted C1-6 alkyl. In certain embodiments, at least one occurrence of R A is unsubstituted C1-6 alkyl. In certain embodiments, at least one occurrence of R A is substituted C1-6 alkyl.
  • R A is substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted tert-butyl, substituted or unsubstituted secbutyl, substituted or unsubstituted isobutyl, substituted or unsubstituted n-pentyl, substituted or unsubstituted 3-pentanyl, substituted or unsubstituted amyl, substituted or unsubstituted neopentyl, substituted or unsubstituted 3-methyl-2-butanyl, substituted or unsubstituted tertamyl, or substituted or unsubstituted n-hcxyl.
  • At least one occurrence of R A is alkyl substituted with an optionally substituted amino group, alkyl substituted with an acyl group, or alkyl substituted with halogen. In certain embodiments, at least one occurrence of R A is alkyl substituted with an optionally substituted amino group. In certain embodiments, at least one occurrence of R A is C1-12 alkyl substituted with an optionally substituted amino group. In certain embodiments, at least one occurrence of R A is C1-6 alkyl substituted with an optionally substituted amino group.
  • At least one occurrence of R A is methyl substituted with an optionally substituted amino group, ethyl substituted with an optionally substituted amino group, n-propyl substituted with an optionally substituted amino group, isopropyl substituted with an optionally substituted amino group, n-butyl substituted with an optionally substituted amino group, tert-butyl substituted with an optionally substituted amino group, sec-butyl substituted with an optionally substituted amino group, isobutyl substituted with an optionally substituted amino group, n- pentyl substituted with an optionally substituted amino group, 3-pentanyl substituted with an optionally substituted amino group, amyl substituted with an optionally substituted amino group, neopentyl substituted with an optionally substituted amino group, 3-methyl-2-butanyl substituted with an optionally substituted amino group, tert-amyl substituted with an optionally substituted amino group, or n-hcxyl substitute
  • At least one occurrence of R A is alkyl substituted with an amino group substituted with an acyl group. In certain embodiments, at least one occurrence of R A is C1-12 alkyl substituted with an amino group substituted with an acyl group. In certain embodiments, at least one occurrence of R A is C1-6 alkyl substituted with an amino group substituted with an acyl group.
  • At least one occurrence of R A is methyl substituted with an amino group substituted with an acyl group, ethyl substituted with an amino group substituted with an acyl group, n-propyl substituted with an amino group substituted with an acyl group, isopropyl substituted with an amino group substituted with an acyl group, n-butyl substituted with an amino group substituted with an acyl group, tert-butyl substituted with an amino group substituted with an acyl group, sec-butyl substituted with an amino group substituted with an acyl group, isobutyl substituted with an amino group substituted with an acyl group, n-pentyl substituted with an amino group substituted with an acyl group, 3-pentanyl substituted with an amino group substituted with an acyl group, amyl substituted with an amino group substituted with an acyl group, neopentyl substituted with an amino group substituted with an acyl group,
  • At least one occurrence of R A is alkyl substituted with an acyl group. In certain embodiments, at least one occurrence of R A is C1-12 alkyl substituted with an acyl group. In certain embodiments, at least one occurrence of R A is C1-6 alkyl substituted with an acyl group.
  • At least one occurrence of R A is methyl substituted with an acyl group, ethyl substituted with an acyl group, n-propyl substituted with an acyl group, isopropyl substituted with an acyl group, n-butyl substituted with an acyl group, tert-butyl substituted with an acyl group, sec-butyl substituted with an acyl group, isobutyl substituted with an acyl group, n-pentyl substituted with an acyl group, 3-pentanyl substituted with an acyl group, amyl substituted with an acyl group, neopentyl substituted with an acyl group, 3-methyl-2- butanyl substituted with an acyl group, tert-amyl substituted with an acyl group, or n-hcxyl substituted with an acyl group.
  • at least one occurrence of R A is C1-12 alkyl substituted with an amide group.
  • at least one occurrence of R A is C1-6 alkyl substituted with an amide group.
  • At least one occurrence of R A is methyl substituted with an amide group, ethyl substituted with an amide group, n-propyl substituted with an amide group, isopropyl substituted with an amide group, n-butyl substituted with an amide group, tert-butyl substituted with an amide group, sec -butyl substituted with an amide group, isobutyl substituted with an amide group, n-pentyl substituted with an amide group, 3-pentanyl substituted with an amide group, amyl substituted with an amide group, neopentyl substituted with an amide group, 3-methyl-2-butanyl substituted with an amide group, tert-amyl substituted with an amide group, or n-hcxyl substituted with an amide group.
  • At least one occurrence of R A is alkyl substituted with halogen. In certain embodiments, at least one occurrence of R A is C1-12 alkyl substituted with halogen. In certain embodiments, at least one occurrence of R A is C1-6 alkyl substituted with halogen.
  • At least one occurrence of R A is methyl substituted with halogen, ethyl substituted with halogen, n-propyl substituted with halogen, isopropyl substituted with halogen, n-butyl substituted with halogen, tert-butyl substituted with halogen, sec -butyl substituted with halogen, isobutyl substituted with halogen, n-pentyl substituted with halogen, 3-pentanyl substituted with halogen, amyl substituted with halogen, neopentyl substituted with halogen, 3- methyl-2-butanyl substituted with halogen, tert-amyl substituted with halogen, or n-hcxyl substituted with halogen.
  • At least one occurrence of R A is alkyl substituted with fluorine, chlorine, or bromine. In certain embodiments, at least one occurrence of R A is alkyl substituted with fluorine. In certain embodiments, at least one occurrence of R A is C1-12 alkyl substituted with fluorine. In certain embodiments, at least one occurrence of R A is Ci-6 alkyl substituted with fluorine.
  • At least one occurrence of R A is methyl substituted with fluorine, ethyl substituted with fluorine, n-propyl substituted with fluorine, isopropyl substituted with fluorine, n-butyl substituted with fluorine, tert-butyl substituted with fluorine, sec-butyl substituted with fluorine, isobutyl substituted with fluorine, n-pentyl substituted with fluorine, 3-pentanyl substituted with fluorine, amyl substituted with fluorine, neopentyl substituted with fluorine, 3-methyl-2-butanyl substituted with fluorine, tert-amyl substituted with fluorine, or n-hcxyl substituted with fluorine.
  • At least one occurrence of R A is ethyl substituted with fluorine. In certain embodiments, at least one occurrence of R A is alkyl substituted with 18 F. In certain embodiments, at least one occurrence of R A is C1-12 alkyl substituted with 18 F. In certain embodiments, at least one occurrence of R A is Ci- 6 alkyl substituted with 18 F.
  • At least one occurrence of R A is methyl substituted with 18 F, ethyl substituted with 18 F, n-propyl substituted with 18 F, isopropyl substituted with 18 F, n-butyl substituted with 18 F, tert-butyl substituted with 18 F, sec -butyl substituted with 18 F, isobutyl substituted with 18 F, n-pentyl substituted with 18 F, 3-pentanyl substituted with 18 F, amyl substituted with 18 F, neopentyl substituted with 18 F, 3-methyl-2- butanyl substituted with 18 F, tert-amyl substituted with 18 F, or n-hcxyl substituted with 18 F.
  • at least one occurrence of R A is ethyl substituted with 18 F.
  • At least one occurrence of R A is optionally substituted C2-12 alkenyl. In certain embodiments, at least one occurrence of R A is optionally substituted C2-6 alkenyl. In certain embodiments, at least one occurrence of R A is substituted or unsubstituted ethenyl, substituted or unsubstituted 1-propenyl, substituted or unsubstituted 2-propenyl, substituted or unsubstituted 1-butenyl, substituted or unsubstituted 2-butenyl, substituted or unsubstituted butadienyl, substituted or unsubstituted pentenyl, substituted or unsubstituted pentadienyl, or substituted or unsubstituted hexenyl.
  • At least one occurrence of R A is optionally substituted C2-12 alkynyl. In certain embodiments, at least one occurrence of R A is optionally substituted C2-6 alkynyl. In certain embodiments, at least one occurrence of R A is substituted or unsubstituted ethynyl, substituted or unsubstituted 1-propynyl, substituted or unsubstituted 2-propynyl, substituted or unsubstituted 1-butynyl, substituted or unsubstituted 2-butynyl, substituted or unsubstituted pentynyl, or substituted or unsubstituted hexynyl.
  • At least one occurrence of R A is optionally substituted heteroC1-12 alkyl. In certain embodiments, at least one occurrence of R A is optionally substituted heteroC1-6 alkyl. In certain embodiments, at least one occurrence of R A is optionally substituted heteroC1-12 alkenyl. In certain embodiments, at least one occurrence of R A is optionally substituted heteroC1-6 alkenyl. In certain embodiments, at least one occurrence of R A is optionally substituted heteroC1-12 alkynyl. In certain embodiments, at least one occurrence of R A is optionally substituted heteroC1-6 alkynyl. In certain embodiments, at least one occurrence of R A is optionally substituted C3-14 cycloalkyl.
  • At least one occurrence of R A is optionally substituted 5-10 membered heterocyclyl. In certain embodiments, at least one occurrence of R A is optionally substituted 6-14 membered aryl. In certain embodiments, at least one occurrence of R A is optionally substituted 5-14 membered heteroaryl. In certain embodiments, at least one occurrence of R A is a nitrogen protecting group when attached to a nitrogen atom. In certain embodiments, at least one occurrence of R A is an oxygen protecting group when attached to an oxygen atom. In certain embodiments, at least one occurrence of R A is a sulfur protecting group when attached to a sulfur atom.
  • each occurrence of R A is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.
  • each occurrence of R B is independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group, or two occurrences of R B are joined together with their intervening atom to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring; and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  • At least one occurrence of R A is
  • R A is wherein: R bl is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.
  • At least one occurrence of R A is , wherein:
  • R 4 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.
  • each occurrence of R B is independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group, or two occurrences of R B are joined together with their intervening atom to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring.
  • At least one occurrence of R B contains at least one radioisotope.
  • At least one occurrence of R B is hydrogen. In certain embodiments, at least one occurrence of R B is optionally substituted acyl. In certain embodiments, at least one occurrence of R B is wherein R bl is as defined herein. In certain embodiments, at least one occurrence of R B is optionally substituted C1-12 alkyl. In certain embodiments, at least one occurrence of R B is optionally substituted C1-6 alkyl. In certain embodiments, at least one occurrence of R B is unsubstituted C1-6 alkyl. In certain embodiments, at least one occurrence of R B is substituted C1-6 alkyl.
  • R B is substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted tert-butyl, substituted or unsubstituted secbutyl, substituted or unsubstituted isobutyl, substituted or unsubstituted n-pentyl, substituted or unsubstituted 3-pentanyl, substituted or unsubstituted amyl, substituted or unsubstituted neopentyl, substituted or unsubstituted 3-methyl-2-butanyl, substituted or unsubstituted tertamyl, or substituted or unsubstituted n-hcxyl.
  • At least one occurrence of R B is optionally substituted C2-12 alkenyl. In certain embodiments, at least one occurrence of R B is optionally substituted C2-6 alkenyl. In certain embodiments, at least one occurrence of R B is substituted or unsubstituted ethenyl, substituted or unsubstituted 1-propenyl, substituted or unsubstituted 2-propenyl, substituted or unsubstituted 1-butenyl, substituted or unsubstituted 2- butenyl, substituted or unsubstituted butadienyl, substituted or unsubstituted pentenyl, substituted or unsubstituted pentadienyl, or substituted or unsubstituted hexenyl.
  • At least one occurrence of R B is optionally substituted C2-12 alkynyl. In certain embodiments, at least one occurrence of R B is optionally substituted C2-6 alkynyl. In certain embodiments, at least one occurrence of R B is substituted or unsubstituted ethynyl, substituted or unsubstituted 1-propynyl, substituted or unsubstituted 2-propynyl, substituted or unsubstituted 1-butynyl, substituted or unsubstituted 2-butynyl, substituted or unsubstituted pentynyl, or substituted or unsubstituted hexynyl.
  • At least one occurrence of R B is optionally substituted heteroC1-12 alkyl. In certain embodiments, at least one occurrence of R B is optionally substituted heteroC1-6 alkyl. In certain embodiments, at least one occurrence of R B is optionally substituted heteroC1-12 alkenyl. In certain embodiments, at least one occurrence of R B is optionally substituted heteroC1-6 alkenyl. In certain embodiments, at least one occurrence of R B is optionally substituted heteroC1-12 alkynyl. In certain embodiments, at least one occurrence of R B is optionally substituted heteroC1-6 alkynyl. In certain embodiments, at least one occurrence of R B is optionally substituted C3-14 cycloalkyl.
  • At least one occurrence of R B is optionally substituted 5-10 membered heterocyclyl. In certain embodiments, at least one occurrence of R B is optionally substituted 6-14 membered aryl. In certain embodiments, at least one occurrence of R B is optionally substituted 5-14 membered heteroaryl. In certain embodiments, at least one occurrence of R B is a nitrogen protecting group when attached to a nitrogen atom. In certain embodiments, at least two occurrences of R B are joined together with their intervening atom to form an optionally substituted 5-10 membered carbocyclic ring. In certain embodiments, at least two occurrences of R B are joined together with their intervening atom to form an optionally substituted 5-10 membered heterocyclic ring.
  • R bl is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.
  • R bl contains at least one radioisotope.
  • R bl is optionally substituted C1-12 alkyl. In certain embodiments, at least one occurrence of R bl is optionally substituted C1-6 alkyl. In certain embodiments, R bl is unsubstituted C1-6 alkyl. In certain embodiments, R bl is substituted C1-6 alkyl.
  • R bl is substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted tert-butyl, substituted or unsubstituted secbutyl, substituted or unsubstituted isobutyl, substituted or unsubstituted n-pentyl, substituted or unsubstituted 3-pentanyl, substituted or unsubstituted amyl, substituted or unsubstituted neopentyl, substituted or unsubstituted 3-methyl-2-butanyl, substituted or unsubstituted tertamyl, or substituted or unsubstituted n-hcxyl.
  • R bl is substituted or unsubstituted methyl. In certain embodiments, R bl is unsubstituted methyl. In certain embodiments, R bl is optionally substituted C2-12 alkenyl. In certain embodiments, R bl is optionally substituted C2-6 alkenyl.
  • R bl is substituted or unsubstituted ethenyl, substituted or unsubstituted 1-propenyl, substituted or unsubstituted 2-propenyl, substituted or unsubstituted 1-butenyl, substituted or unsubstituted 2-butenyl, substituted or unsubstituted butadienyl, substituted or unsubstituted pentenyl, substituted or unsubstituted pentadienyl, or substituted or unsubstituted hexenyl.
  • R bl is optionally substituted C2-12 alkynyl.
  • R bl is optionally substituted C2-6 alkynyl. In certain embodiments, R bl is substituted or unsubstituted ethynyl, substituted or unsubstituted 1- propynyl, substituted or unsubstituted 2-propynyl, substituted or unsubstituted 1-butynyl, substituted or unsubstituted 2-butynyl, substituted or unsubstituted pentynyl, or substituted or unsubstituted hexynyl. In certain embodiments, R bl is optionally substituted heteroC1-12 alkyl. In certain embodiments, R bl is optionally substituted heteroC1-6 alkyl.
  • R bl is optionally substituted heteroC1-12 alkenyl. In certain embodiments, R bl is optionally substituted heteroC1-6 alkenyl. In certain embodiments, R bl is optionally substituted heteroC1-12 alkynyl. In certain embodiments, R bl is optionally substituted heteroC1-6 alkynyl. In certain embodiments, R bl is optionally substituted C3-14 cycloalkyl. In certain embodiments, R bl is optionally substituted 5-10 membered heterocyclyl.
  • R bl is optionally substituted aryl or optionally substituted heteroaryl. In certain embodiments, R bl is optionally substituted aryl. In certain embodiments, R bl is aryl substituted with halogen. In certain embodiments, R bl is aryl substituted with fluorine. In certain embodiments, R bl is aryl substituted with 18 F. In certain embodiments, R bl is optionally substituted 6-14 membered aryl. In certain embodiments, R bl is 6-14 membered aryl substituted with halogen. In certain embodiments, R bl is 6-14 membered aryl substituted with fluorine.
  • R bl is 6-14 membered aryl substituted with 18 F. In certain embodiments, R bl is phenyl substituted with fluorine. In certain embodiments, R bl is phenyl substituted with 18 F. In certain embodiments, R bl is F . In certain embodiments, R bl is certain embodiments, R bl is
  • R bl is certain embodiments, R bl is In certain embodiments, R bl is optionally substituted heteroaryl. In certain embodiments,
  • R bl is heteroaryl substituted with halogen. In certain embodiments, R bl is heteroaryl substituted with fluorine. In certain embodiments, R bl is heteroaryl substituted with 18 F. In certain embodiments, R bl is optionally substituted 5-14 membered heteroaryl. In certain embodiments, R bl is 5-14 membered heteroaryl substituted with halogen. In certain embodiments, R bl is 5-14 membered heteroaryl substituted with fluorine. In certain embodiments, R bl is 5-14 membered heteroaryl substituted with 18 F. In certain embodiments, R bl is pyridyl substituted with fluorine. In certain embodiments, R bl is pyridyl substituted with 18 F. In certain embodiments, R bl is
  • R bl is In certain embodiments, R bl is
  • R bl is In certain embodiments, R bl is
  • R bl is In certain embodiments, R bl is
  • R bl is In certain embodiments, R bl is certain embodiments, R bl is certain embodiments, R bl is In certain embodiments, R bl is certain embodiments, R bl is embodiments, R bl is 18 F . In certain embodiments, R bl is . In certain embodiments, R bl is n
  • n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  • n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. In certain embodiments, n is 4. In certain embodiments, n is 5. In certain embodiments, n is 6. In certain embodiments, n is 7. In certain embodiments, n is 8. In certain embodiments, n is 9. In certain embodiments, n is 10.
  • n is 2 and R bl is optionally substituted aryl or optionally substituted heteroaryl. In certain embodiments, n is 2 and R bl is optionally substituted aryl. In certain embodiments, n is 2 and R bl is aryl substituted with halogen. In certain embodiments, n is 2 and R bl is aryl substituted with fluorine. In certain embodiments, n is 2 and R bl is aryl substituted with 18 F. In certain embodiments, n is 2 and R bl is optionally substituted 6-14 membered aryl. In certain embodiments, n is 2 and R bl is 6-14 membered aryl substituted with halogen.
  • n is 2 and R bl is 6-14 membered aryl substituted with fluorine. In certain embodiments, n is 2 and R bl is 6-14 membered aryl substituted with 18 F. In certain embodiments, n is 2 and R bl is optionally substituted heteroaryl. In certain embodiments, n is 2 and R bl is heteroaryl substituted with halogen. In certain embodiments, n is 2 and R bl is heteroaryl substituted with fluorine. In certain embodiments, n is 2 and R bl is heteroaryl substituted with 18 F. In certain embodiments, n is 2 and R bl is optionally substituted 5-14 membered heteroaryl.
  • n is 2 and R bl is 5-14 membered heteroaryl substituted with halogen. In certain embodiments, n is 2 and R bl is 5-14 membered heteroaryl substituted with fluorine. In certain embodiments, n is 2 and R bl is 5-14 membered heteroaryl substituted with 18 F. In certain embodiments, n is 2 and m is 5. In certain embodiments, n is 2, m is 5, and at least one occurrence of Y 1 is CH2. In certain embodiments, n is 2 and (Y ⁇ m is (CtDs.
  • n is 2, (Y ⁇ m is (CtDs, and R 1 is -N(R A )2 and contains at least one radioisotope. In certain embodiments, n is 2, (Y ⁇ m is (CtDs, and R 1 is -NHR A and contains at least one radioisotope. In certain embodiments, n is 2, (Y ⁇ m is (CtDs, R 1 is -NHR A and contains at least one radioisotope, and R A is N(R h . j n certain embodiments, n is 2, (Y ⁇ m is (CtDs, R 1 is -N(R A )2 and contains at least one radioisotope. In certain embodiments, n is 2, (Y ⁇ m is (CtDs, R 1 is -N(R A )2 and contains at least one radioisotope. In certain embodiments, n is 2, (Y ⁇ m is (CtDs, R 1 is -N(R A )2 and contains at least
  • NHR A and contains at least one radioisotope
  • R A is NHR B .
  • j n certain embodiments, n is 2,
  • Y ⁇ m is (CH2)5, R 1 is -NHR A and contains at least one radioisotope, and R A is R b1 .
  • n is 2, (Y ⁇ m is (CtDs, R 1 is -NHR A and contains at least one radioisotope,
  • R A is R b1 , and R bl is optionally substituted aryl or optionally substituted heteroaryl.
  • n is 2, (Y ⁇ m is (CtDs, R 1 is -NHR A and contains at least one radioisotope, o ⁇ NH
  • R A is R b1 , and R bl is optionally substituted aryl.
  • n is 2, (Y ⁇ m is
  • R 1 is -NHR A and contains at least one radioisotope
  • R A is R b1
  • R bl is aryl substituted with halogen.
  • n is 2
  • (Y ⁇ m is (CtDs, R 1 is -NHR A and
  • O ⁇ z NH contains at least one radioisotope
  • R A is R b1
  • R bl is aryl substituted with fluorine.
  • n is 2, (Y ⁇ m is (CtDs, R 1 is -NHR A and contains at least one radioisotope, o ⁇ NH
  • R A is R b1 , and R bl is aryl substituted with 18 F.
  • n is 2, (Y ⁇ m is (()> o ⁇ NH
  • R 1 is -NHR A and contains at least one radioisotope
  • R A is R b1
  • R bl is optionally substituted 6-14 membered aryl.
  • n is 2, (Y ⁇ m is (CFDs, R 1 is -NHR A
  • R A is R b1
  • R bl is 6-14 membered aryl substituted with halogen.
  • n is 2, (Y ⁇ m is (CFDs, R 1 is -NHR A and
  • O ⁇ z NH contains at least one radioisotope
  • R A is R b1
  • R bl is 6-14 membered aryl substituted with fluorine.
  • n is 2, (Y ⁇ m is (CFDs, R 1 is -NHR A and contains at least
  • R A O ⁇ z NH one radioisotope
  • R A is R b1
  • R bl is 6-14 membered aryl substituted with 18 F.
  • n is 2
  • (Y ⁇ m is (CFDs, R 1 is -NHR A and contains at least one radioisotope, R A is
  • R b1 , and R bl is phenyl substituted with fluorine.
  • n is 2, (Y ⁇ m is
  • R 1 is -NHR A and contains at least one radioisotope
  • R A is R b1
  • R bl is phenyl substituted with 18 F.
  • n is 2, (Y ⁇ m is (CFDs, R 1 is -NHR A and contains at
  • R A is R b1
  • R bl is F
  • n is 2,
  • n 2
  • (Y ⁇ m is (CFDs)
  • R 1 is -NHR A and contains at least (( ⁇ F ⁇ x
  • R 1 is -NHR A and contains at least one radioisotope
  • R A is R b1
  • R bl is phenyl substituted with 18 F.
  • n is 2
  • (Y ⁇ m is (CFDs, R 1 is -NHR A and contains at
  • R A is R b1
  • R bl is 18 F .
  • n is 2,
  • O ⁇ / NH (Y ⁇ m is (CH2)S
  • R 1 is -NHR A and contains at least one radioisotope
  • R A is R b1
  • R bl is
  • n 2, (Y ⁇ m is (CH2)5, R 1 is -NHR A and contains at
  • R A is R b1
  • R bl is
  • n 2, (Y ⁇ m is (CH2)5, R 1 is -NHR A and contains at least one
  • R A is R b1 , and R bl is optionally substituted heteroaryl.
  • n is 2, (Y ⁇ m is (CH2)5, R 1 is -NHR A and contains at least one radioisotope, R A is
  • R b1 , and R bl is heteroaryl substituted with halogen.
  • n is 2, (Y ⁇ m is
  • n 2, (Y ⁇ m is (CH2)5, R 1 is -NHR A and o ⁇ NH contains at least one radioisotope, R A is R b1 , and R bl is heteroaryl substituted with 18 F.
  • n 2, (Y ⁇ m is (CFDs, R 1 is -NHR A and contains at least one radioisotope,
  • R A is R b1 , and R bl is optionally substituted 5-14 membered heteroaryl.
  • n is 2, (Y ⁇ m is (CFDs, R 1 is -NHR A and contains at least one radioisotope, R A is
  • n 2
  • (Y ⁇ m is (CFDs, R 1 is -NHR A and contains at least one radioisotope, R A is
  • R b1 , and R bl is 5-14 membered heteroaryl substituted with fluorine.
  • n is 2, (Y ⁇ m is (CFDs, R 1 is -NHR A and contains at least one radioisotope, R A is
  • R b1 , and R bl is 5-14 membered heteroaryl substituted with 18 F.
  • n is 5-14 membered heteroaryl substituted with 18 F.
  • O ⁇ / NH is 2, (Y ⁇ m is (CH2)S, R 1 is -NHR A and contains at least one radioisotope, R A is R b1 , and R bl is pyridyl substituted with fluorine.
  • n is 2, (Y ⁇ m is (CFDs, R 1 is -NHR A
  • R A is R b1
  • R bl is pyridyl substituted with 18 F.
  • n is 2, (Y ⁇ m is (CFDs, R 1 is -NHR A and contains at least one radioisotope, x
  • R A is R b1
  • R bl is F vi — & .
  • n is 2, (Y ⁇ m is (CFDs, R 1 is - 0 ⁇ NH
  • R A is R b1
  • R bl is .
  • n is 2, (Y ⁇ m is (CFDs, R 1 is -NHR A and contains at least one radioisotope, R A is
  • n is 2, (Y ⁇ m is (CFDs, R 1 is -NHR A and contains at least one radioisotope, R A is . In certain embodiments, n is 2, (Y ⁇ m is (CFDs, R 1 is -NHR A and contains at least one radioisotope, R A is
  • R b1 , and R bl is .
  • n is 2, (Y ⁇ m is (CFDs, R 1 is -NHR A
  • R A O ⁇ NH and contains at least one radioisotope
  • R A is R b1
  • R bl is N .
  • n is 2
  • (Y ⁇ m is (CFDs, R 1 is -NHR A and contains at least one radioisotope, R A is
  • R b1 , and R bl is F .
  • n is 2, (Y ⁇ m is (CFDs, R 1 is -NHR A
  • R A O ⁇ NH F and contains at least one radioisotope
  • R A is R b1
  • R bl is TM .
  • n is 2
  • (Y ⁇ m is (CFDs, R 1 is -NHR A and contains at least one radioisotope, R A is
  • R b1 , and R bl is .
  • n is 2, (Y ⁇ m is (CFDs, R 1 is -NHR A and
  • O ⁇ z NH contains at least one radioisotope
  • R A is R b1
  • R bl is .
  • n is 2, (Y ⁇ m is (CFDs, R 1 is -NHR A and contains at least one radioisotope, R A is ⁇ V H
  • R b1 , and R bl is .
  • n is 2, (Y ⁇ m is (CtDs, R 1 is -NHR A cw NH
  • R A 18 and contains at least one radioisotope
  • R A is R b1
  • R bl is .
  • n is 2
  • (Y ⁇ m is (CtDs, R 1 is -NHR A and contains at least one radioisotope, R A is
  • R b1 , and R bl is .
  • n is 2, (Y ⁇ m is (CtDs, R 1 is -NHR A
  • n 2
  • (Y ⁇ m is (CtDs, R 1 is -NHR A and contains at least one radioisotope, R A is
  • R b1 , and R bl is .
  • n is 2, (Y ⁇ m is (CtDs, R 1 is -NHR A
  • R A O ⁇ z NH and contains at least one radioisotope
  • R A is R b1
  • R bl is 18 F .
  • n is 2
  • (Y ⁇ m is (CtDs, R 1 is -NHR A and contains at least one radioisotope, R A is
  • R b1 , and R bl is .
  • n is 2, (Y ⁇ m is (CtDs, R 1 is -
  • R 3 contains at least one radioisotope.
  • R 3 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.
  • R 3 is optionally substituted C1-12 alkyl.
  • R 3 is optionally substituted C1-6 alkyl.
  • R 3 is unsubstituted C1-6 alkyl.
  • R 3 is substituted C1-6 alkyl.
  • R 3 is substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted tert-butyl, substituted or unsubstituted .sec-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted n-pentyl, substituted or unsubstituted 3-pentanyl, substituted or unsubstituted amyl, substituted or unsubstituted neopentyl, substituted or unsubstituted 3-methyl-2-butanyl, substituted or unsubstituted tert-amyl, or substituted or unsubstituted n-hcxyl.
  • R 3 is substituted or unsubstituted methyl. In certain embodiments, R 3 is unsubstituted methyl. In certain embodiments, R 3 is optionally substituted C2-12 alkenyl. In certain embodiments, R 3 is optionally substituted C2-6 alkenyl.
  • R 3 is substituted or unsubstituted ethenyl, substituted or unsubstituted 1- propenyl, substituted or unsubstituted 2-propenyl, substituted or unsubstituted 1-butenyl, substituted or unsubstituted 2-butenyl, substituted or unsubstituted butadienyl, substituted or unsubstituted pentenyl, substituted or unsubstituted pentadienyl, or substituted or unsubstituted hexenyl.
  • R 3 is optionally substituted C2-12 alkynyl. In certain embodiments, R 3 is optionally substituted C2-6 alkynyl.
  • R 3 is substituted or unsubstituted ethynyl, substituted or unsubstituted 1-propynyl, substituted or unsubstituted 2- propynyl, substituted or unsubstituted 1-butynyl, substituted or unsubstituted 2-butynyl, substituted or unsubstituted pentynyl, or substituted or unsubstituted hexynyl.
  • R 3 is optionally substituted heteroCi -12 alkyl.
  • R 3 is optionally substituted heteroCi -6 alkyl.
  • R 3 is optionally substituted heteroC1-12 alkenyl.
  • R 3 is optionally substituted heteroC1-6 alkenyl. In certain embodiments, R 3 is optionally substituted heteroCi -12 alkynyl. In certain embodiments, R 3 is optionally substituted heteroCi -6 alkynyl. In certain embodiments, R 3 is optionally substituted C3-14 cycloalkyl. In certain embodiments, R 3 is optionally substituted 6-14 membered aryl. In certain embodiments, R 3 is optionally substituted 5-14 membered heteroaryl. In certain embodiments, R 3 is optionally substituted 5-10 membered heterocyclyl. In certain embodiments, R 3 is optionally substituted azacyclooctyne. In certain embodiments, R 3 is an optionally substituted aza-dibenzocyclooctyne.
  • R cl is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.
  • each occurrence of R c is independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two occurrences of R c are joined together with their intervening atom to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring.
  • At least one occurrence of R c contains at least one radioisotope. In certain embodiments, at least one occurrence of R c is hydrogen. In certain embodiments, at least one occurrence of R c is optionally substituted acyl. In certain embodiments, at least one occurrence of R c is optionally substituted C1-12 alkyl. In certain embodiments, at least one occurrence of R c is optionally substituted C1-6 alkyl. In certain embodiments, at least one occurrence of R c is unsubstituted C1-6 alkyl. In certain embodiments, at least one occurrence of R c is substituted C1-6 alkyl.
  • R c is substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted tert-butyl, substituted or unsubstituted secbutyl, substituted or unsubstituted isobutyl, substituted or unsubstituted n-pentyl, substituted or unsubstituted 3-pentanyl, substituted or unsubstituted amyl, substituted or unsubstituted neopentyl, substituted or unsubstituted 3-methyl-2-butanyl, substituted or unsubstituted tertamyl, or substituted or unsubstituted n-hcxyl.
  • At least one occurrence of R c is optionally substituted C2-6 alkenyl. In certain embodiments, at least one occurrence of R c is substituted or unsubstituted ethenyl, substituted or unsubstituted 1-propenyl, substituted or unsubstituted 2-propenyl, substituted or unsubstituted 1-butenyl, substituted or unsubstituted 2- butenyl, substituted or unsubstituted butadienyl, substituted or unsubstituted pentenyl, substituted or unsubstituted pentadienyl, or substituted or unsubstituted hexenyl.
  • At least one occurrence of R c is optionally substituted C2-6 alkynyl. In certain embodiments, at least one occurrence of R c is substituted or unsubstituted ethynyl, substituted or unsubstituted 1- propynyl, substituted or unsubstituted 2-propynyl, substituted or unsubstituted 1-butynyl, substituted or unsubstituted 2-butynyl, substituted or unsubstituted pentynyl, or substituted or unsubstituted hexynyl. In certain embodiments, at least one occurrence of R c is optionally substituted heteroCi -6 alkyl.
  • At least one occurrence of R c is optionally substituted heteroC1-6 alkenyl. In certain embodiments, at least one occurrence of R c is optionally substituted heteroC1-12 alkynyl. In certain embodiments, at least one occurrence of R c is optionally substituted heteroC1-6 alkynyl. In certain embodiments, at least one occurrence of R c is optionally substituted C3-14 cycloalkyl. In certain embodiments, at least one occurrence of R c is optionally substituted 5-10 membered heterocyclyl. In certain embodiments, at least one occurrence of R c is optionally substituted 6-14 membered aryl.
  • At least one occurrence of R c is optionally substituted 5-14 membered heteroaryl. In certain embodiments, at least one occurrence of R c is a nitrogen protecting group. In certain embodiments, at least one occurrence of R c is an oxygen protecting group. In certain embodiments, at least one occurrence of R c is a sulfur protecting group. In certain embodiments, at least two occurrences of R c are joined together with their intervening atom to form an optionally substituted 5-10 membered heterocyclic ring. In certain embodiments, at least two occurrences of R c are joined together with their intervening atom to form an optionally substituted 5-14 membered heteroaryl ring.
  • R 3 is -N(R C )2 and two occurrences of R c are joined together with their intervening atom to form an optionally substituted 5-10 membered heterocyclyl. In certain embodiments, R 3 is -N(R C )2 and two occurrences of R c are joined together with their intervening atom to form an optionally substituted 8 membered heterocyclyl. In certain embodiments, R 3 is -N(R C )2 and two occurrences of R c are joined together with their intervening atom to form an optionally substituted azacyclooctyne.
  • R 3 is -N(R C ) 2 and two occurrences of R c are joined together with their intervening atom to form an optionally substituted aza-dibenzocyclooctyne. In certain embodiments, R 3 is -N(R C )2 and two occurrences of R c are joined together with their intervening atom to form
  • each occurrence of R cl is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.
  • At least one occurrence of R cl contains at least one radioisotope.
  • R cl is optionally substituted alkyl. In certain embodiments, R cl is alkyl substituted with halogen. In certain embodiments, R cl is alkyl substituted with fluorine, chlorine, or bromine. In certain embodiments, R cl is alkyl substituted with fluorine. In certain embodiments, R cl is optionally substituted C1-12 alkyl. In certain embodiments, R cl is C1-12 alkyl substituted with halogen. In certain embodiments, R cl is optionally substituted C1-6 alkyl. In certain embodiments, R cl is C1-6 alkyl substituted with halogen. In certain embodiments, R cl is unsubstituted C1-6 alkyl.
  • R cl is substituted C1-6 alkyl. In certain embodiments, R cl is optionally substituted C1-6 alkyl optionally substituted with one or more halogen or optionally substituted alkyl groups. In certain embodiments, R cl is substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted tert-butyl, substituted or unsubstituted .sec-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted n-pentyl, substituted or unsubstituted 3-pentanyl, substituted or unsubstituted amyl, substituted or unsubstituted neopentyl, substituted
  • R cl is methyl substituted with halogen, ethyl substituted with halogen, n-propyl substituted with halogen, isopropyl substituted with halogen, n-butyl substituted with halogen, tert-butyl substituted with halogen, sec -butyl substituted with halogen, isobutyl substituted with halogen, n-pentyl substituted with halogen, 3-pentanyl substituted with halogen, amyl substituted with halogen, neopentyl substituted with halogen, 3- methyl-2-butanyl substituted with halogen, tert-amyl substituted with halogen, or n-hcxyl substituted with halogen.
  • R cl is C1-12 alkyl substituted with fluorine. In certain embodiments, R cl is C1-6 alkyl substituted with fluorine. In certain embodiments, R cl is methyl substituted with fluorine, ethyl substituted with fluorine, n-propyl substituted with fluorine, isopropyl substituted with fluorine, n-butyl substituted with fluorine, tert-butyl substituted with fluorine, sec -butyl substituted with fluorine, isobutyl substituted with fluorine, n- pentyl substituted with fluorine, 3-pentanyl substituted with fluorine, amyl substituted with fluorine, neopentyl substituted with fluorine, 3-methyl-2-butanyl substituted with fluorine, tertamyl substituted with fluorine, or n-hcxyl substituted with fluorine.
  • R cl is ethyl substituted with fluorine. In certain embodiments, R cl is alkyl substituted with 18 F. In certain embodiments, R cl is C1-12 alkyl substituted with 18 F. In certain embodiments, R cl is C1-6 alkyl substituted with 18 F.
  • R cl is methyl substituted with 18 F, ethyl substituted with 18 F, n-propyl substituted with 18 F, isopropyl substituted with 18 F, n-butyl substituted with 18 F, tert-butyl substituted with 18 F, sec -butyl substituted with 18 F, isobutyl substituted with 18 F, n-pentyl substituted with 18 F, 3-pentanyl substituted with 18 F, amyl substituted with 18 F, neopentyl substituted with 18 F, 3-methyl-2-butanyl substituted with 18 F, tertamyl substituted with 18 F, or n-hcxyl substituted with 18 F.
  • R cl is ethyl substituted with 18 F.
  • R 3 is optionally substituted alkyl.
  • R 3 is optionally substituted alkyl.
  • R 3 is optionally substituted alkyl.
  • R 3 is optionally substituted alkyl.
  • R cl is alkyl substituted with halogen.
  • R 3 is
  • R cl is alkyl substituted with fluorine, chlorine, or bromine. In certain embodiments, R 3 is substituted with fluorine. In certain embodiments, R 3 is and R cl is optionally substituted C1-12 alkyl. In certain embodiments, R 3 is , and R cl is C1-12 alkyl substituted with halogen. In certain embodiments, R 3 is
  • R cl is optionally substituted C1-6 alkyl. In certain with halogen.
  • R 3 is unsubstituted C1-6 alkyl.
  • R 3 is and R cl is substituted C1-6 alkyl.
  • R 3 is
  • R cl is optionally substituted C1-6 alkyl optionally substituted with one or more halogen or optionally substituted alkyl groups.
  • R 3 is , and R cl is substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted tertbutyl, substituted or unsubstituted sec-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted n-pentyl, substituted or unsubstituted 3-pentanyl, substituted or unsubstituted amyl, substituted or unsubstituted neopentyl, substituted or unsubstituted 3-methyl-2-butanyl
  • R cl is methyl substituted with halogen, ethyl substituted with halogen, n-propyl substituted with halogen, isopropyl substituted with halogen, n-butyl substituted with halogen, tert-butyl substituted with halogen, sec-butyl substituted with halogen, isobutyl substituted with halogen, n-pentyl substituted with halogen, 3- pentanyl substituted with halogen, amyl substituted with halogen, neopentyl substituted with halogen, 3-methyl-2-butanyl substituted with halogen, tert-amyl substituted with halogen, or n- hexyl substituted with halogen.
  • R 3 is
  • R cl is C1-12 alkyl substituted with fluorine.
  • R 3 is
  • R C1 is C1-6 alkyl substituted with fluorine.
  • R 3 is substituted with fluorine, ethyl substituted with fluorine, n-propyl substituted with fluorine, isopropyl substituted with fluorine, n-butyl substituted with fluorine, tert-butyl substituted with fluorine, sec-butyl substituted with fluorine, isobutyl substituted with fluorine, n-pentyl substituted with fluorine, 3-pentanyl substituted with fluorine, amyl substituted with fluorine, neopentyl substituted with fluorine, 3-methyl-2-butanyl substituted with fluorine, tert-amyl substituted with fluorine, or n-hcxyl substituted with fluorine.
  • R 3 is substituted with fluorine, ethyl substituted with fluorine, n-propyl substituted with fluorine, isopropyl substituted
  • R cl is ethyl substituted with fluorine.
  • R cl is alkyl substituted with
  • R 3 is substituted with 18 F. In certain embodiments, R 3 is
  • R cl is C1-6 alkyl substituted with 18 F.
  • R 3 is , and R cl is methyl substituted with 18 F, ethyl substituted with 18 F, n-propyl substituted with 18 F, isopropyl substituted with 18 F, n-butyl substituted with 18 F, tert-butyl substituted with 18 F, sec-butyl substituted with 18 F, isobutyl substituted with 18 F, n-pentyl substituted with 18 F, 3-pentanyl substituted with 18 F, amyl substituted with 18 F, neopentyl substituted with 18 F, 3-methyl-2-butanyl substituted with 18 F, tert-amyl substituted with 18 F, or n- hexyl substituted with 18 F.
  • R 3 is
  • R cl is optionally substituted C2-6 alkenyl.
  • R cl is substituted or unsubstituted ethenyl, substituted or unsubstituted 1-propenyl, substituted or unsubstituted 2-propenyl, substituted or unsubstituted 1-butenyl, substituted or unsubstituted 2-butenyl, substituted or unsubstituted butadienyl, substituted or unsubstituted pentenyl, substituted or unsubstituted pentadienyl, or substituted or unsubstituted hexenyl.
  • R cl is optionally substituted C2-6 alkynyl. In certain embodiments, R cl is substituted or unsubstituted ethynyl, substituted or unsubstituted 1-propynyl, substituted or unsubstituted 2-propynyl, substituted or unsubstituted 1-butynyl, substituted or unsubstituted 2- butynyl, substituted or unsubstituted pentynyl, or substituted or unsubstituted hexynyl. In certain embodiments, R cl is optionally substituted heteroCi -6 alkyl.
  • R cl is optionally substituted heteroCi -6 alkenyl. In certain embodiments, R cl is optionally substituted heteroC1-12 alkynyl. In certain embodiments, R cl is optionally substituted heteroC1-6 alkynyl. In certain embodiments, R cl is optionally substituted C3-14 cycloalkyl. In certain embodiments, R cl is optionally substituted 5-10 membered heterocyclyl. In certain embodiments, R cl is optionally substituted 6-14 membered aryl. In certain embodiments, R cl is optionally substituted 5-14 membered heteroaryl.
  • R 4 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.
  • R 4 contains at least one radioisotope.
  • R 4 is optionally substituted aryl. In certain embodiments, R 4 is aryl substituted with optionally substituted alkyl. In certain embodiments, R 4 is 6-14 membered aryl substituted with optionally substituted alkyl. In certain embodiments, R 4 is aryl substituted with optionally substituted alkyl substituted with optionally substituted heterocyclyl. In certain embodiments, R 4 is 6-14 membered aryl substituted with optionally substituted alkyl substituted with optionally substituted heterocyclyl. In certain embodiments, R 4 is phenyl substituted with optionally substituted alkyl substituted with optionally substituted heterocyclyl. In certain embodiments, R 4 comprises a chelating moiety.
  • R 4 comprises dodecane tetraacetic acid (DOTA). In certain embodiments, R 4 comprises l,4,7-triazacyclononane-l,4,7- triacetic acid (NOTA). In certain embodiments, R 4 is
  • R 4 is
  • R 4 comprises
  • R 4 comprises a copper radioisotope
  • R 4 comprises ⁇ Cu. In certain embodiments, R 4
  • R 4 comprises a chelate of
  • R 4 comprises a chelate of CO 2 H and 67 Cu.
  • n 2
  • (Y ⁇ m is (CH 2 )5
  • R 1 is -NHR A and contains at least one
  • n 2
  • (Y ⁇ m is (CH 2 )5
  • R 1 is -NHR A
  • R A is R 4 , and R 4 is optionally substituted aryl or optionally substituted heteroaryl.
  • n is 2, (Y ⁇ m is (CH 2 )5, R 1 is -NHR A
  • n 2
  • (Y ⁇ m is (CH 2 )5
  • R 1 is -NHR A and contains at least one radioisotope
  • Q NH
  • R A is R 4 , and R 4 is aryl substituted with optionally substituted alkyl.
  • n is 2, (Y ⁇ m is (CtDs, R 1 is -NHR A and contains at least one radioisotope, R A is
  • R 4 , and R 4 is 6-14 membered aryl substituted with optionally substituted alkyl.
  • n is 2, (Y ⁇ m is (CtDs, R 1 is -NHR A and contains at least one radioisotope, R A is
  • R 4 is aryl substituted with optionally substituted alkyl substituted with optionally substituted heterocyclyl.
  • n is 2, (Y ⁇ m is (CtDs, R 1 is -NHR A and
  • Z NH contains at least one radioisotope
  • R A is R 4
  • R 4 is 6-14 membered aryl substituted with optionally substituted alkyl substituted with optionally substituted heterocyclyl.
  • n is 2, (Y ⁇ m is (CtDs, R 1 is -NHR A and contains at least one radioisotope, R A is
  • R 4 , and R 4 is phenyl substituted with optionally substituted alkyl substituted with optionally substituted heterocyclyl.
  • n is 2, (Y ⁇ m is (CtDs, R 1 is -NHR A
  • R A is R 4
  • n 2
  • (Y ⁇ m is (CtDs, R 1 is -NHR A and contains at least one Q ,NH
  • R A is R 4 , and R 4 comprises embodiments, n is 2, (Y ⁇ m is (CtDs, R 1 is -NHR A and contains at least one radioisotope, R A is
  • R 4 , and R 4 comprises a copper radioisotope (e.g., ⁇ Cu, 67 Cu).
  • n is
  • R A is R 4
  • R 4 comprises 67 Cu.
  • n is 2,
  • Y ⁇ m is (CH2)S
  • R 1 is -NHR A and contains at least one radioisotope
  • R A is R 4
  • R 4 comprises and ⁇ Cu.
  • n is 2, (Y ⁇ m is
  • R 1 is -NHR A and contains at least one radioisotope
  • R A is R 4
  • R 4 comprises and 67 Cu.
  • n is 2
  • (Y ⁇ m is (CtDs, R 1 is - Q Z NH
  • R A is R 4
  • R 4 comprises a chelate of and 64 Cu.
  • n is 2, (Y ⁇ m is (CtDs, R 1 is -
  • R A is R 4
  • R 4 comprises a chelate of
  • p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In certain embodiments, p is 0. In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is 3. In certain embodiments, p is 4. In certain embodiments, p is 5. In certain embodiments, p is 6. In certain embodiments, p is 7. In certain embodiments, p is 8. In certain embodiments, p is 9. In certain embodiments, p is 10.
  • p is 2 and m is 5. In certain embodiments, p is 2, m is 5, and at least one occurrence of Y 1 is CH2. In certain embodiments, p is 2 and (Y ⁇ m is (CtDs. In certain embodiments, p is 2, (Y ⁇ m is (CtDs, and R 1 is -N(R A )2 and contains at least one radioisotope. In certain embodiments, p is 2, (Y ⁇ m is (CtDs, and R 1 is -NHR A and contains at least one radioisotope. In certain embodiments, p is 2, (Y ⁇ m is (CtDs, R 1 is -NHR A and contains at least one radioisotope. In certain embodiments, p is 2, (Y ⁇ m is (CtDs, R 1 is -NHR A and contains at least
  • R A is R .
  • p is 2, (Y ⁇ m is (CtDs, R 1 is -NHR A it and contains at least one radioisotope, R A is R , and R 3 is optionally substituted 5-14 membered heteroaryl.
  • p is 2, (Y ⁇ m is (CH2K R 1 is -NHR A and contains at least one radioisotope, R A is R 3 , and R 3 is optionally substituted 5-10 membered heterocyclyl.
  • p is 2, (Y ⁇ m is (CtDs, R 1 is -NHR A and contains at least one radioisotope, R A is R 3 , and R 3 is optionally substituted azacyclooctyne. In certain embodiments, p is 2, (Y ⁇ m is (CtDs, R 1 is -NHR A and contains at least one radioisotope, R A is
  • R 3 is an optionally substituted aza-dibenzocyclooctyne.
  • p is
  • p is 2, (Y ⁇ m is (CtDs, R 1 is -
  • R cl is ethyl substituted with fluorine.
  • p is 2,
  • R cl is alkyl substituted with 18 F.
  • p is 2
  • (Y ⁇ m is (CtDs, R 1 is -NHR A and contains at least one radioisotope, R A is , and R cl is C1-12 alkyl substituted with 18 F.
  • p is 2, (Y ⁇ m is (CFhjs, R 1 is -NHR A and contains at least one radioisotope, R A is R substituted with 18 F.
  • p is 2, (Y ⁇ m is (CFLjs, R 1 is -NHR A and contains at least one radioisotope, R A is R 3 methyl substituted with 18 F, ethyl substituted with 18 F, n-propyl substituted with 18 F, isopropyl substituted with 18 F, n-butyl substituted with 18 F, tert-butyl substituted with 18 F, sec -butyl substituted with 18 F, isobutyl substituted with 18 F, n-pentyl substituted with 18 F, 3-pentanyl substituted with 18 F, amyl substituted with 18 F, neopentyl substituted with 18 F, 3-methyl-2- butanyl substituted with 18 F, tert-amyl substituted with 18 F,
  • R cl is ethyl substituted with
  • p is 2, (Y ⁇ m is (CFLjs, R 1 is -NHR A and contains at least one radioisotope, R A is R , R 3 is -N(R C ) 2 , and two occurrences of R c are joined together with their intervening atom to form an optionally substituted 5-10 membered heterocyclyl.
  • p is 2, (Y ⁇ m is (CFhjs, R 1 is -NHR A and contains at least one radioisotope, R A is
  • R 3 ° , R 3 is -N(R C ) 2 , and two occurrences of R c are joined together with their intervening atom to form an optionally substituted 8 membered heterocyclyl.
  • p is 2, (Y ⁇ m is (CH2)S, R 1 is -NHR A and contains at least one radioisotope, R A is R 3 , R 3 is -N(R C )2, and two occurrences of R c are joined together with their intervening atom to form an optionally substituted azacyclooctyne.
  • p is 2, (Y ⁇ m is (CH2)5, R 1 is -NHR A and contains at least one radioisotope, R A is R 3 , R 3 is -N(R C )2, and two occurrences of R c are joined together with their intervening atom to form an optionally substituted aza- dibenzocyclooctyne.
  • p is 2, (Y ⁇ m is (Cthjs, R 1 is -NHR A and contains at least one radioisotope, R A is R 3 , R 3 is -N(R C )2, and two occurrences of R c are joined together with their intervening atom to form embodiments, p is 2, (Y ⁇ m is (Ctkjs, R 1 is -NHR A and contains at least one radioisotope, R A is
  • R 3 ° , R 3 is -N(R C ) 2 , two occurrences of R c are joined together with their intervening atom to
  • R cl is optionally substituted alkyl.
  • p is 2
  • (Y ⁇ m is (Ctkjs, R 1 is -NHR A and contains at least one radioisotope, R A is
  • R 3 ° , R 3 is -N(R C ) 2 , two occurrences of R c are joined together with their intervening atom to
  • R cl is alkyl substituted with halogen.
  • p is 2
  • (Y ⁇ m is (Ctkjs, R 1 is -NHR A and contains at least one radioisotope, , R 3 is -N(R C ) 2 , two occurrences of R c are joined together with their intervening
  • R cl is alkyl substituted with fluorine, chlorine, or bromine. In certain embodiments, R cl is alkyl substituted with fluorine. In certain embodiments, p is 2, (Y ⁇ m is (Ctkjs, R 1 is -NHR A and contains at least one radioisotope, R A is
  • R 3 is -N(R C ) 2 , two occurrences of R c are joined together with their intervening atom to
  • R cl is optionally substituted C1-12 alkyl.
  • p is 2
  • (Y ⁇ m is (Ctkjs, R 1 is -NHR A and contains at least one radioisotope,
  • R 3 is -N(R C ) 2 , two occurrences of R c are joined together with their intervening
  • R cl is C1-12 alkyl substituted with halogen.
  • p is 2, (Y ⁇ m is (Ctkjs, R 1 is -NHR A and contains at least one radioisotope, R A is R , R 3 is -N(R C ) 2 , two occurrences of R c are joined together with their intervening atom to form substituted C1-6 alkyl.
  • p is 2, (Y ⁇ m is (Cthjs, R 1 is -NHR A and contains 'VP at least one radioisotope, R A is R 3 , R 3 is -N(R C )2, two occurrences of R c are joined together alkyl substituted with halogen.
  • p is 2, (Y ⁇ m is (Ctkjs, R 1 is -NHR A and
  • R A is R 3
  • R 3 is -N(R C )2
  • two occurrences of R c are joined unsubstituted C1-6 alkyl.
  • p is 2
  • (Y ⁇ m is (Cthjs, R 1 is -NHR A and
  • R A is R 3
  • R 3 is -N(R C )2
  • two occurrences of R c are joined substituted C1-6 alkyl.
  • p is 2
  • (Y ⁇ m is (Cthjs, R 1 is -NHR A and contains
  • R A is R 3 , R 3 is -N(R C )2, two occurrences of R c are joined together optionally substituted C1-6 alkyl optionally substituted with one or more halogen or optionally substituted alkyl groups.
  • p is 2, (Y ⁇ m is (Ctkjs, R 1 is -NHR A and contains at least one radioisotope, R A is R 3 , R 3 is -N(R C )2, two occurrences of R c are joined
  • p is 2, (Y ⁇ m is (CH2)5, R 1 is -NHR A and contains at least one radioisotope, R A is R 3 , R 3 is -N(R C )2, two occurrences of R c are joined together with their intervening atom to form substituted with halogen, ethyl substituted with halogen, n-propyl substituted with halogen, isopropyl substituted with halogen, n-butyl substituted with halogen, tert-butyl substituted with halogen, sec-butyl substituted with halogen, isobutyl substituted with halogen, n-pentyl substituted with halogen, 3-pentanyl substituted with halogen, amyl substituted with halogen, neopentyl substituted with halogen, 3-methyl-2-butanyl substituted with halogen, tert-amyl substituted with halogen, or n-hcx
  • R d-N s two occurrences of R c are joined together with their intervening atom to form N
  • R cl is C1-12 alkyl substituted with fluorine.
  • p is 2, (Y ⁇ m is (CH2)S, R 1 is -NHR A and contains at least one radioisotope, R A is R 3 , R 3 is - N(R C ) 2 , two occurrences of R c are joined together with their intervening atom to form
  • R cl is C1-6 alkyl substituted with fluorine.
  • p is 2
  • (Y ⁇ m is (Ctkjs, R 1 is -NHR A and contains at least one radioisotope,
  • R 3 is -N(R C ) 2 , two occurrences of R c are joined together with their intervening
  • R cl is methyl substituted with fluorine, ethyl substituted with fluorine, n-propyl substituted with fluorine, isopropyl substituted with fluorine, n-butyl substituted with fluorine, tert-butyl substituted with fluorine, .sec-butyl substituted with fluorine, isobutyl substituted with fluorine, n-pentyl substituted with fluorine, 3- pentanyl substituted with fluorine, amyl substituted with fluorine, neopentyl substituted with fluorine, 3-methyl-2-butanyl substituted with fluorine, tert-amyl substituted with fluorine, or n- hexyl substituted with fluorine.
  • p is 2, (Y ⁇ m is (CH2K R 1 is -NHR A and contains at least one radioisotope, R A is R , R 3 is -N(R C ) 2 , two occurrences of R c are joined together with their intervening atom to form ethyl substituted with fluorine.
  • p is 2, (Y ⁇ m is (CH2K R 1 is -NHR A and 'VP contains at least one radioisotope, R A is R 3 , R 3 is -N(R C )2, two occurrences of R c are joined alkyl substituted with 18 F.
  • R cl is C1-12 alkyl substituted with 18 F.
  • p is 2, (Y ⁇ m is (CFhjs, R 1 is -NHR A and contains at least one radioisotope,
  • R A is R 3 0
  • R 3 is -N(R C ) 2
  • two occurrences of R c are joined together with their intervening
  • p is 2, (Y ⁇ m is (CFhjs, R 1 is -NHR A and contains at least one
  • R A is R 3
  • R 3 is -N(R C )2
  • two occurrences of R c are joined together with their with 18 F, ethyl substituted with 18 F, n-propyl substituted with 18 F, isopropyl substituted with 18 F, n-butyl substituted with 18 F, tert-butyl substituted with 18 F, sec-butyl substituted with 18 F, isobutyl substituted with 18 F, n-pentyl substituted with 18 F, 3-pentanyl substituted with 18 F, amyl substituted with 18 F, neopentyl substituted with 18 F, 3-methyl-2-butanyl substituted with 18 F, tertamyl substituted with 18 F, or n-hexyl substituted with 18 F.
  • p is 2, (Y ⁇ m is 2, (Y ⁇ m is
  • R 1 is -NHR A and contains at least one radioisotope
  • R A is R
  • R 3 is -N(R C )2
  • two occurrences of R c are joined together with their intervening atom to form
  • each occurrence of R 2 is independently hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or two occurrences of R 2 are joined together with their intervening atom to form an optionally substituted carbocyclic ring or optionally substituted heterocyclic ring.
  • At least one occurrence of R 2 is hydrogen. In certain embodiments, R 2 is halogen. In certain embodiments, R 2 is fluorine, chlorine, or bromine. In certain embodiments, at least one occurrence of R 2 is optionally substituted acyl. In certain embodiments, at least one occurrence of R 2 is optionally substituted C1-12 alkyl. In certain embodiments, at least one occurrence of R 2 is optionally substituted C1-6 alkyl. In certain embodiments, at least one occurrence of R 2 is unsubstituted C1-6 alkyl. In certain embodiments, at least one occurrence of R 2 is substituted C1-6 alkyl.
  • At least one occurrence of R 2 is substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted tert-butyl, substituted or unsubstituted secbutyl, substituted or unsubstituted isobutyl, substituted or unsubstituted n-pentyl, substituted or unsubstituted 3-pentanyl, substituted or unsubstituted amyl, substituted or unsubstituted neopentyl, substituted or unsubstituted 3-methyl-2-butanyl, substituted or unsubstituted tertamyl, or substituted or unsubstituted n-hcxyl.
  • At least one occurrence of R 2 is substituted or unsubstituted methyl. In certain embodiments, at least one occurrence of R 2 is unsubstituted methyl. In certain embodiments, at least one occurrence of R 2 is optionally substituted C2-12 alkenyl. In certain embodiments, at least one occurrence of R 2 is optionally substituted C2-6 alkenyl.
  • At least one occurrence of R 2 is substituted or unsubstituted ethenyl, substituted or unsubstituted 1-propenyl, substituted or unsubstituted 2- propenyl, substituted or unsubstituted 1-butenyl, substituted or unsubstituted 2-butenyl, substituted or unsubstituted butadienyl, substituted or unsubstituted pentenyl, substituted or unsubstituted pentadienyl, or substituted or unsubstituted hexenyl. In certain embodiments, at least one occurrence of R 2 is optionally substituted C2-12 alkynyl.
  • At least one occurrence of R 2 is optionally substituted C2-6 alkynyl. In certain embodiments, at least one occurrence of R 2 is substituted or unsubstituted ethynyl, substituted or unsubstituted 1-propynyl, substituted or unsubstituted 2-propynyl, substituted or unsubstituted 1-butynyl, substituted or unsubstituted 2-butynyl, substituted or unsubstituted pentynyl, or substituted or unsubstituted hexynyl. In certain embodiments, at least one occurrence of R 2 is optionally substituted heteroCi- 12 alkyl.
  • At least one occurrence of R 2 is optionally substituted heteroC1-6 alkyl. In certain embodiments, at least one occurrence of R 2 is optionally substituted heteroC1-12 alkenyl. In certain embodiments, at least one occurrence of R 2 is optionally substituted heteroC1-6 alkenyl. In certain embodiments, at least one occurrence of R 2 is optionally substituted heteroCi 12 alkynyl. In certain embodiments, at least one occurrence of R 2 is optionally substituted heteroC1-6 alkynyl. In certain embodiments, at least one occurrence of R 2 is optionally substituted C3-14 cycloalkyl. In certain embodiments, at least one occurrence of R 2 is optionally substituted 5-10 membered heterocyclyl.
  • At least one occurrence of R 2 is optionally substituted 6-14 membered aryl. In certain embodiments, at least one occurrence of R 2 is optionally substituted 5-14 membered heteroaryl. In certain embodiments, at least two occurrences of R 2 are joined together with their intervening atom to form an optionally substituted 5-10 membered carbocyclic ring. In certain embodiments, at least two occurrences of R 2 are joined together with their intervening atom to form an optionally substituted 5-10 membered heterocyclic ring.
  • At least two occurrences of R 2 are optionally substituted C1-12 alkyl. In certain embodiments, at least two occurrences of R 2 are optionally substituted C1-6 alkyl. In certain embodiments, at least two occurrences of R 2 are unsubstituted C1-6 alkyl. In certain embodiments, at least two occurrences of R 2 are substituted C1-6 alkyl.
  • At least two occurrences of R 2 are substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted tert-butyl, substituted or unsubstituted secbutyl, substituted or unsubstituted isobutyl, substituted or unsubstituted n-pentyl, substituted or unsubstituted 3-pentanyl, substituted or unsubstituted amyl, substituted or unsubstituted neopentyl, substituted or unsubstituted 3-methyl-2-butanyl, substituted or unsubstituted tert- amyl, or substituted or unsubstituted u-hcxyl.
  • R 2 are substituted or un
  • At least three occurrences of R 2 are optionally substituted C1-12 alkyl. In certain embodiments, at least three occurrences of R 2 are optionally substituted C1-6 alkyl. In certain embodiments, at least three occurrences of R 2 are unsubstituted C1-6 alkyl. In certain embodiments, at least three occurrences of R 2 are substituted C1-6 alkyl.
  • At least three occurrences of R 2 are substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted tert-butyl, substituted or unsubstituted sec-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted n- pentyl, substituted or unsubstituted 3-pentanyl, substituted or unsubstituted amyl, substituted or unsubstituted neopentyl, substituted or unsubstituted 3-methyl-2-butanyl, substituted or unsubstituted tert-amyl, or substituted or unsubstituted n-hcxyl.
  • R 2 are substituted or
  • At least four occurrences of R 2 are optionally substituted C1-12 alkyl. In certain embodiments, at least four occurrences of R 2 are optionally substituted C1-6 alkyl. In certain embodiments, at least four occurrences of R 2 are unsubstituted C1-6 alkyl. In certain embodiments, at least four occurrences of R 2 are substituted C1-6 alkyl.
  • At least four occurrences of R 2 are substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted tert-butyl, substituted or unsubstituted sec-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted n- pentyl, substituted or unsubstituted 3-pentanyl, substituted or unsubstituted amyl, substituted or unsubstituted neopentyl, substituted or unsubstituted 3-methyl-2-butanyl, substituted or unsubstituted tert-amyl, or substituted or unsubstituted n-hcxyl.
  • R 2 are substituted or
  • a provided compound of Formula I contains at least one radioisotope (z.e., R 1 in Formula I contains at least one radioisotope).
  • the at least one radioisotope is n C, 18 F, 13 N, 15 O, ⁇ Cu, 67 Ga, 68 Ga, 75 Se, 81m Kr, 82 Rb, " m Tc, ni In, 123 I, 125 I, 131 I, 133 Xe.
  • the at least one radioisotope is n C, 18 F, 13 N, 15 O, 64 Cu, 67 Cu, 67 Ga, 68 Ga, 75 Se, 81m Kr, 82 Rb, " m Tc, in In, 123 I, 125 I, 131 I, 133 Xe. In certain embodiments, the at least one radioisotope is n C, 18 F, 13 N, 15 O, 75 Se, 123 I, 125 I, or 131 I.
  • the at least one radioisotope is n C. In certain embodiments, the at least one radioisotope is 18 F. In certain embodiments, the at least one radioisotope is 13 N. In certain embodiments, the at least one radioisotope is 15 O. In certain embodiments, the at least one radioisotope is 75 Se. In certain embodiments, the at least one radioisotope is 123 I. In certain embodiments, the at least one radioisotope is 125 I. In certain embodiments, the at least one radioisotope is 131 I. In certain embodiments, the at least one radioisotope is ⁇ Cu. In certain embodiments, the at least one radioisotope is 67 Cu.
  • the at least one radioisotope is 67 Ga. In certain embodiments, the at least one radioisotope is 68 Ga. In certain embodiments, the at least one radioisotope is 81m Kr. In certain embodiments, the at least one radioisotope is 82 Rb. In certain embodiments, the at least one radioisotope is " m Tc. In certain embodiments, the at least one radioisotope is in In. In certain embodiments, the at least one radioisotope is 133 Xe.
  • the provided compound is of Formula I-a-i: or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or prodrug thereof.
  • the provided compound is of Formula I-a-ii:
  • the provided compound is of Formula I-a-iii:
  • the provided compound is of Formula I-b:
  • the provided compound is of Formula I-b-i:
  • the provided compound is of Formula I-c: (I-c), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or prodrug thereof.
  • the provided compound is of Formula I-c-i: or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or prodrug thereof.
  • the provided compound is of Formula I-d: or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or prodrug thereof.
  • the provided compound is of Formula I-d-i: (I-d-i), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or prodrug thereof.
  • the provided compound is of Formula I-e: or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or prodrug thereof.
  • the provided compound is of Formula I-e-i: or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or prodrug thereof.
  • the provided compound is of Formula I-f: or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or prodrug thereof.
  • the provided compound is of Formula I-f-i: or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or prodrug thereof.
  • the provided compound is of Formula I-g: stereoisomer, or prodrug thereof.
  • the provided compound is of Formula I-g-i:
  • the provided compound is of Formula I-h: or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or prodrug thereof.
  • the provided compound is of Formula I-h-i: or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or prodrug thereof.
  • the provided compound is of Formula I-h-ii or Formula I-h-iii:
  • the provided compound is of Formula I-j: z NH
  • R4 d-j or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or prodrug thereof.
  • the provided compound is of Formula I-j-i: zNH R 4 d-j-i), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or prodrug thereof.
  • any of the formulae disclosed herein are subgenera of Formula
  • the provided compound is of formula:
  • the provided compound is of formula: or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or prodrug thereof.
  • the provided compound is of formula: or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or prodrug thereof.
  • the provided compound is of formula:
  • the provided compound is of formula:
  • the provided compound is of formula: or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or prodrug thereof.
  • the provided compound degrades less than 10% 1 minute after preparing the compound. In certain embodiments, the provided compound degrades less than 10% 5 minutes after preparing the compound. In certain embodiments, the provided compound degrades less than 10% 10 minutes after preparing the compound. In certain embodiments, the provided compound degrades less than 10% 15 minutes after preparing the compound. In certain embodiments, the provided compound degrades less than 10% 20 minutes after preparing the compound. In certain embodiments, the provided compound degrades less than 10% 25 minutes after preparing the compound. In certain embodiments, the provided compound degrades less than 10% 30 minutes after preparing the compound. In certain embodiments, the provided compound degrades less than 10% 35 minutes after preparing the compound.
  • the provided compound degrades less than 10% 40 minutes after preparing the compound. In certain embodiments, the provided compound degrades less than 10% 45 minutes after preparing the compound. In certain embodiments, the provided compound degrades less than 10% 50 minutes after preparing the compound. In certain embodiments, the provided compound degrades less than 10% 55 minutes after preparing the compound. In certain embodiments, the provided compound degrades less than 10% 1 hour after preparing the compound. In certain embodiments, the provided compound degrades less than 10% 2 hours after preparing the compound. In certain embodiments, the provided compound degrades less than 10% 3 hours after preparing the compound. In certain embodiments, the provided compound degrades less than 10% 4 hours after preparing the compound.
  • the provided compound degrades less than 10% 5 hours after preparing the compound. In certain embodiments, the provided compound degrades less than 10% 6 hours after preparing the compound. In certain embodiments, the provided compound degrades less than 10% 7 hours after preparing the compound. In certain embodiments, the provided compound degrades less than 10% 8 hours after preparing the compound. In certain embodiments, the provided compound degrades less than 10% 9 hours after preparing the compound. In certain embodiments, the provided compound degrades less than 10% 10 hours after preparing the compound. In certain embodiments, the provided compound degrades less than 10% 11 hours after preparing the compound. In certain embodiments, the provided compound degrades less than 10% 12 hours after preparing the compound.
  • the provided compound degrades less than 10% 16 hours after preparing the compound. In certain embodiments, the provided compound degrades less than 10% 20 hours after preparing the compound. In certain embodiments, the provided compound degrades less than 10% 1 day after preparing the compound. In certain embodiments, the provided compound degrades less than 10% 2 days after preparing the compound. In certain embodiments, the provided compound degrades less than 10% 3 days after preparing the compound. In certain embodiments, the provided compound degrades less than 10% 4 days after preparing the compound. In certain embodiments, the provided compound degrades less than 10% 5 days after preparing the compound. In certain embodiments, the provided compound degrades less than 10% 6 days after preparing the compound.
  • the provided compound degrades less than 10% 1 week after preparing the compound. In certain embodiments, the provided compound degrades less than 10% 1 month after preparing the compound. In certain embodiments, the provided compound degrades less than 10% 6 months after preparing the compound. In certain embodiments, the provided compound degrades less than 10% 1 year after preparing the compound.
  • the composition is stable for at least 1 minute. In certain embodiments, the composition is stable for at least 5 minutes. In certain embodiments, the composition is stable for at least 10 minutes. In certain embodiments, the composition is stable for at least 15 minutes. In certain embodiments, the composition is stable for at least 20 minutes. In certain embodiments, the composition is stable for at least 25 minutes. In certain embodiments, the composition is stable for at least 30 minutes. In certain embodiments, the composition is stable for at least 35 minutes. In certain embodiments, the composition is stable for at least 40 minutes. In certain embodiments, the composition is stable for at least 45 minutes. In certain embodiments, the composition is stable for at least 50 minutes. In certain embodiments, the composition is stable for at least 55 minutes.
  • the composition is stable for at least 1 hour. In certain embodiments, the composition is stable for at least 2 hours. In certain embodiments, the composition is stable for at least 3 hours. In certain embodiments, the composition is stable for at least 4 hours. In certain embodiments, the composition is stable for at least 5 hours. In certain embodiments, the composition is stable for at least 6 hours. In certain embodiments, the composition is stable for at least 7 hours. In certain embodiments, the composition is stable for at least 8 hours. In certain embodiments, the composition is stable for at least 9 hours. In certain embodiments, the composition is stable for at least 10 hours. In certain embodiments, the composition is stable for at least 11 hours. In certain embodiments, the composition is stable for at least 12 hours.
  • the composition is stable for at least 16 hours. In certain embodiments, the composition is stable for at least 20 hours. In certain embodiments, the composition is stable for at least one day. In certain embodiments, the composition is stable for at least two days. In certain embodiments, the composition is stable for at least three days. In certain embodiments, the composition is stable for at least four days. In certain embodiments, the composition is stable for at least five days. In certain embodiments, the composition is stable for at least six days. In certain embodiments, the composition is stable for at least one week. In certain embodiments, the composition is stable for at least 1 month. In certain embodiments, the composition is stable for at least 6 months. In certain embodiments, the composition is stable for at least 1 year.
  • the composition is stable for at least 1 minute at room temperature (e.g., about 20-40 °C). In certain embodiments, the composition is stable for at least 5 minutes at room temperature (e.g., about 20-40 °C). In certain embodiments, the composition is stable for at least 10 minutes at room temperature (e.g., about 20-40 °C). In certain embodiments, the composition is stable for at least 15 minutes at room temperature (e.g., about 20-40 °C). In certain embodiments, the composition is stable for at least 20 minutes at room temperature (e.g., about 20-40 °C). In certain embodiments, the composition is stable for at least 25 minutes at room temperature (e.g., about 20-40 °C).
  • the composition is stable for at least 30 minutes at room temperature (e.g., about 20-40 °C). In certain embodiments, the composition is stable for at least 35 minutes at room temperature (e.g., about 20-40 °C). In certain embodiments, the composition is stable for at least 40 minutes at room temperature (e.g., about 20-40 °C). In certain embodiments, the composition is stable for at least 45 minutes at room temperature (e.g., about 20-40 °C). In certain embodiments, the composition is stable for at least 50 minutes at room temperature (e.g., about 20-40 °C). In certain embodiments, the composition is stable for at least 55 minutes at room temperature (e.g., about 20-40 °C).
  • the composition is stable for at least 1 hour at room temperature (e.g., about 20-40 °C). In certain embodiments, the composition is stable for at least 2 hours at room temperature (e.g., about 20-40 °C). In certain embodiments, the composition is stable for at least 3 hours at room temperature (e.g., about 20-40 °C). In certain embodiments, the composition is stable for at least 4 hours at room temperature (e.g., about 20-40 °C). In certain embodiments, the composition is stable for at least 5 hours at room temperature (e.g., about 20-40 °C). In certain embodiments, the composition is stable for at least 6 hours at room temperature (e.g., about 20- 40 °C).
  • the composition is stable for at least 7 hours at room temperature (e.g., about 20-40 °C). In certain embodiments, the composition is stable for at least 8 hours at room temperature (e.g., about 20-40 °C). In certain embodiments, the composition is stable for at least 9 hours at room temperature (e.g., about 20-40 °C). In certain embodiments, the composition is stable for at least 10 hours at room temperature (e.g., about 20-40 °C). In certain embodiments, the composition is stable for at least 11 hours at room temperature (e.g., about 20- 40 °C). In certain embodiments, the composition is stable for at least 12 hours at room temperature (e.g., about 20-40 °C).
  • the composition is stable for at least 16 hours at room temperature (e.g., about 20-40 °C). In certain embodiments, the composition is stable for at least 20 hours at room temperature (e.g., about 20-40 °C). In certain embodiments, the composition is stable for at least one day at room temperature (e.g., about 20-40 °C). In certain embodiments, the composition is stable for at least two days at room temperature (e.g., about 20-40 °C). In certain embodiments, the composition is stable for at least three days at room temperature (e.g., about 20-40 °C). In certain embodiments, the composition is stable for at least four days at room temperature (e.g., about 20-40 °C).
  • the composition is stable for at least five days at room temperature (e.g., about 20-40 °C). In certain embodiments, the composition is stable for at least six days at room temperature (e.g., about 20-40 °C). In certain embodiments, the composition is stable for at least one week at room temperature (e.g., about 20-40 °C). In certain embodiments, the composition is stable for at least 1 month at room temperature (e.g., about 20-40 °C). In certain embodiments, the composition is stable for at least 6 months at room temperature (e.g., about 20-40 °C). In certain embodiments, the composition is stable for at least 1 year at room temperature (e.g., about 20-40 °C).
  • the composition is stable at about 0-40 °C. In certain embodiments, the composition is stable at about 0-20 °C. In certain embodiments, the composition is stable at about 20-40 °C. In certain embodiments, the composition is stable at about 0-10 °C. In certain embodiments, the composition is stable at about 10-20 °C. In certain embodiments, the composition is stable at about 20-30 °C. In certain embodiments, the composition is stable at about 30-40 °C. In certain embodiments, the composition is stable at about 0-5 °C. In certain embodiments, the composition is stable at about 5-10 °C. In certain embodiments, the composition is stable at about 10-15 °C. In certain embodiments, the composition is stable at about 15-20 °C.
  • the composition is stable at about 20-25 °C. In certain embodiments, the composition is stable at about 25-30 °C. In certain embodiments, the composition is stable at about 30-35 °C. In certain embodiments, the composition is stable at about 35-40 °C. In certain embodiments, the composition is stable at about 4 °C. In certain embodiments, the composition is stable at about 23.5 °C. In certain embodiments, the composition is stable at about 37 °C.
  • a compound or a composition comprising a compound of Formula (I) is stable when the compound degrades less than 1%, less than 2%, less than 3%, less than 4%, less than 5%, less than 6%, less than 7%, less than 8%, less than 9%, less than 10%, less than 15%, less than 20%, less than 25%, less than 30%, less than 35%, less than 40%, less than 45%, less than 50%, less than 55%, less than 60%, less than 70%, less than 80%, or less than 90% at any temperature and timepoint recited in the above paragraphs.
  • a provided compound (a compound described herein, a compound of the present disclosure) is a compound of Formula I or I', or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.
  • a provided compound is a compound of Formula I or I', or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.
  • a provided compound is a compound of Formula I or I', or a pharmaceutically acceptable salt or tautomer thereof.
  • a provided compound is a compound of Formula I or I', or a pharmaceutically acceptable salt thereof.
  • a provided compound (a compound described herein, a compound of the present disclosure) is a compound of Formula I, or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.
  • a provided compound is a compound of Formula I, or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.
  • a provided compound is a compound of Formula I, or a pharmaceutically acceptable salt or tautomer thereof.
  • a provided compound is a compound of Formula I, or a pharmaceutically acceptable salt thereof.
  • compositions comprising a provided compound, and optionally a pharmaceutically acceptable excipient.
  • the pharmaceutical composition described herein comprises a provided compound, and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition comprises an effective amount of the provided compound.
  • the effective amount is a therapeutically effective amount.
  • the effective amount is a prophylactically effective amount.
  • the effective amount is an amount effective for diagnosing a disease in a subject in need thereof.
  • the effective amount is an amount effective for treating a disease in a subject in need thereof.
  • the effective amount is an amount effective for preventing a disease in a subject in need thereof.
  • the effective amount is an amount effective for reducing the risk of developing a disease in a subject in need thereof.
  • the effective amount is an amount effective for reducing the size of a tumor (e.g., in a subject, tissue, biological sample, or cell). In certain embodiments, the effective amount is an amount effective for promoting apoptosis in a subject in need thereof or in a cell, tissue, or biological sample, wherein the cell, tissue, or biological sample is in vivo. In certain embodiments, the effective amount is an amount effective for promoting apoptosis in a subject in need thereof or in a cell, tissue, or biological sample, wherein the cell, tissue, or biological sample is in vitro.
  • the subject is an animal. In certain embodiments, the subject is a human. In certain embodiments, the subject is a human aged 18 years or older. In certain embodiments, the subject is a human aged 12-18 years, exclusive. In certain embodiments, the subject is a human aged 2-12 years, inclusive. In certain embodiments, the subject is a human younger than 2 years. In certain embodiments, the subject is a non-human animal. In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a non-human mammal. In certain embodiments, the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat.
  • the subject is a companion animal, such as a dog or cat.
  • the subject is a livestock animal, such as a cow, pig, horse, sheep, or goat.
  • the subject is a zoo animal.
  • the subject is a research animal, such as a rodent (e.g., mouse, rat), dog, pig, or non-human primate.
  • the animal is a genetically engineered animal.
  • the animal is a transgenic animal (e.g., transgenic mice and transgenic pigs).
  • the subject is a fish or reptile.
  • the pharmaceutical composition is for use in diagnosing a disease. In certain embodiments, the pharmaceutical composition is for use in treating a disease. In certain embodiments, the pharmaceutical composition is for use in preventing a disease.
  • a provided compound or pharmaceutical composition, as described herein, can be administered in combination with one or more additional pharmaceutical agents (e.g., therapeutically and/or prophylactically active agents).
  • the provided compounds or pharmaceutical compositions can be administered in combination with additional pharmaceutical agents that improve their activity (e.g., activity (e.g., potency and/or efficacy) in diagnosing a disease in a subject in need thereof, treating a disease in a subject in need thereof, in preventing a disease in a subject in need thereof, and/or in reducing the risk of developing a disease in a subject in need thereof), improve bioavailability, improve safety, reduce drug resistance, reduce and/or modify metabolism, inhibit excretion, and/or modify distribution in a subject or cell.
  • additional pharmaceutical agents e.g., therapeutically and/or prophylactically active agents.
  • additional pharmaceutical agents that improve their activity (e.g., activity (e.g., potency and/or efficacy) in diagnosing a disease in a subject in need thereof, treating
  • the additional pharmaceutical agents employed may achieve a desired effect for the same disorder, and/or it may achieve different effects.
  • a pharmaceutical composition described herein including a provided compound described herein and an additional pharmaceutical agent exhibit a synergistic effect that is absent in a pharmaceutical composition including one of the provided compounds and the additional pharmaceutical agent, but not both.
  • the additional pharmaceutical agent achieves a desired effect for the same disorder.
  • the additional pharmaceutical agent achieves different effects.
  • the provided compound or pharmaceutical composition can be administered concurrently with, prior to, or subsequent to one or more additional pharmaceutical agents, which are different from the compound or pharmaceutical composition and may be useful as, e.g., combination therapies.
  • Pharmaceutical agents include diagnostic agents.
  • Pharmaceutical agents include therapeutically active agents.
  • Pharmaceutical agents also include prophylactically active agents.
  • Pharmaceutical agents include small organic molecules such as drug compounds (e.g., compounds approved for human or veterinary use by the U.S.
  • the additional pharmaceutical agent is a pharmaceutical agent useful for diagnosing, treating, and/or preventing a disease.
  • Each additional pharmaceutical agent may be administered at a dose and/or on a time schedule determined for that pharmaceutical agent.
  • the additional pharmaceutical agents may also be administered together with each other and/or with the compound or pharmaceutical composition described herein in a single dose or administered separately in different doses.
  • the particular combination to employ in a regimen will take into account compatibility of the compound described herein with the additional pharmaceutical agent(s) and/or the desired diagnostic, therapeutic, and/or prophylactic effect to be achieved.
  • it is expected that the additional pharmaceutical agent(s) in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually.
  • the additional pharmaceutical agents include, but are not limited to, anti-proliferative agents, anti-cancer agents, cytotoxic agents, anti-angiogenesis agents, anti-inflammatory agents, and immunosuppressants.
  • the additional pharmaceutical agent is an antiinflammatory agent.
  • the additional pharmaceutical agent is an immunotherapy.
  • the additional pharmaceutical agent is an antiproliferative agent.
  • the additional pharmaceutical agent is an anti-cancer agent.
  • the anti-cancer agents include, but are not limited to, epigenetic or transcriptional modulators (e.g., DNA methyltransferase inhibitors, HD AC inhibitors, lysine methyltransferase inhibitors), antimitotic drugs (e.g., taxanes and vinca alkaloids), cell signaling pathway inhibitors (e.g., tyrosine protein kinase inhibitors), modulators of protein stability (e.g., proteasome inhibitors), Hsp90 inhibitors, glucocorticoids, all-trans retinoic acids, anti-estrogens (e.g., tamoxifen, raloxifene, and megestrol), LHRH agonists (e.g., goscrclin and leuprolide), antiandrogens (e.g.
  • epigenetic or transcriptional modulators e.g., DNA methyltransferase inhibitors, HD AC inhibitors, lysine methyltransferase inhibitors
  • flutamide and bicalutamide flutamide and bicalutamide
  • photodynamic therapies e.g., vertoporfin (BPD- MA), phthalocyanine, photosensitizer Pc4, and demethoxy-hypocrellin A (2BA-2-DMHA)
  • nitrogen mustards e.g., cyclophosphamide, ifosfamide, trofosfamide, chlorambucil, estramustine, and melphalan
  • nitrosoureas e.g., carmustine (BCNU) and lomustine (CCNU)
  • alkylsulphonates e.g., busulfan and treosulfan
  • triazenes e.g.
  • dacarbazine, temozolomide platinum containing compounds (e.g. cisplatin, carboplatin, oxaliplatin), vinca alkaloids (e.g. vincristine, vinblastine, vindesine, and vinorelbine), taxoids (e.g.
  • paclitaxel or a paclitaxel equivalent such as nanoparticle albumin-bound paclitaxel (ABRAXANE), docosahexaenoic acid bound-paclitaxel (DHA-paclitaxel, Taxoprexin), polyglutamate bound-paclitaxel (PG-paclitaxel, paclitaxel poliglumex, CT-2103, XYOTAX), the tumor-activated prodrug (TAP) ANG1005 (Angiopep-2 bound to three molecules of paclitaxel), paclitaxel-EC- 1 (paclitaxel bound to the erbB2-recognizing peptide EC-1), and glucose-conjugated paclitaxel, e.g., 2 '-paclitaxel methyl 2- glucopyranosyl succinate; docetaxel, taxol), epipodophyllins (e.g.
  • ABRAXANE nanoparticle albumin-bound paclitaxel
  • DHFR inhibitors e.g., methotrexate, dichloromethotrexate, trimetrexate, edatrexate
  • IMP dehydrogenase inhibitors e.g., mycophenolic acid, tiazofurin, ribavirin, and EICAR
  • ribonuclotide reductase inhibitors e.g., hydroxyurea and deferoxamine
  • uracil analogs e.g., 5 -fluorouracil (5-FU)
  • floxuridine doxifluridine, ratitrexed, tegafur-uracil, capecitabine
  • cytosine analogs e.g., cytarabine
  • the additional pharmaceutical agent is an immunotherapy.
  • the immunotherapy is useful in the treatment of a cancer.
  • immunotherapies include, but are not limited to, T-cell therapies, interferons, cytokines (e.g., tumor necrosis factor, interferon a, interferon y), vaccines, hematopoietic growth factors, monoclonal serotherapy, immuno stimulants and/or immunodulatory agents (e.g., IL-1, 2, 4, 6, or 12), immune cell growth factors (e.g., GM-CSF) and antibodies.
  • the immunotherapy is a T-cell therapy.
  • the T-cell therapy is chimeric antigen receptor T cells (CAR-T).
  • the immunotherapy is an antibody.
  • the antibody is an anti-PD-1 antibody, an anti-PD-Ll antibody, an anti- CTLA-4 antibody, an anti-TIM3 antibody, an anti-OX40 antibody, an anti-GITR antibody, an anti-LAG-3 antibody, an anti-CD137 antibody, an anti-CD27 antibody, an anti-CD28 antibody, an anti-CD28H antibody, an anti-CD30 antibody, an anti-CD39 antibody, an anti-CD40 antibody, an anti-CD47 antibody, an anti-CD48 antibody, an anti-CD70 antibody, an anti-CD73 antibody, an anti-CD96 antibody, an anti-CD160 antibody, an anti-CD200 antibody, an anti- CD244 antibody, an anti-ICOS antibody, an anti-TNFRSF25 antibody, an anti-TMIGD2 antibody, an anti-DNAMl antibody, an anti-BTLA antibody, an anti-LIGHT antibody, an anti- TIGIT antibody, an anti- VISTA antibody, an anti-HVEM antibody, an anti-
  • the antibody is pembrolizumab, nivolumab, pidilizumab, ipilimumab, tremelimumab, durvalumab, atezolizumab, avelumab, PF-06801591, utomilumab, PDR001, PBF-509, MGB453, LAG525, AMP-224, INCSHR1210, INCAGN1876, INCAGN1949, samalizumab, PF-05082566, urelumab, lirilumab, lulizumab, BMS-936559, BMS-936561, BMS-986004, BMS-986012, BMS-986016, BMS-986178, IMP321, IPH2101, IPH2201, varilumab, ulocuplumab, monalizumab, MEDI0562, MEDI0680, MEDI1873, MEDI6383,
  • At least one of the additional pharmaceutical agents is a cytotoxic agent.
  • at least one of the additional pharmaceutical agents is venetoclax, azacitidine, bortezomib, cladribine, cytarabine, doxorubicin, eribulin, etoposide, everolimus, ixabepilone, mitoxantrone, ixazomib, panobinostat, pemetrexed, SN-38, or topotecan, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.
  • At least one of the additional pharmaceutical agents is nivolumab, pidilizumab, pembrolizumab, MEDL 0680, REGN2810, AMP-224, atezolizumab, durvalumab, BMS-936559, avelumab, CA-170, ipilimumab, or tremelimumab, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.
  • the provided compounds or pharmaceutical compositions can be administered in combination with an anti-cancer therapy including, but not limited to, surgery, radiation therapy, transplantation (e.g., stem cell transplantation, bone marrow transplantation), immunotherapy, and chemotherapy.
  • an anti-cancer therapy including, but not limited to, surgery, radiation therapy, transplantation (e.g., stem cell transplantation, bone marrow transplantation), immunotherapy, and chemotherapy.
  • the provided compound or pharmaceutical composition is a solid. In certain embodiments, the provided compound or pharmaceutical composition is a powder. In certain embodiments, the provided compound or pharmaceutical composition can be dissolved in a liquid to make a solution. In certain embodiments, the provided compound or pharmaceutical composition is dissolved in water to make an aqueous solution. In certain embodiments, the pharmaceutical composition is a liquid for parental injection. In certain embodiments, the pharmaceutical composition is a liquid for oral administration (e.g., ingestion). In certain embodiments, the pharmaceutical composition is a liquid (e.g., aqueous solution) for intravenous injection. In certain embodiments, the pharmaceutical composition is a liquid (e.g., aqueous solution) for subcutaneous injection.
  • compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include the steps of bringing the composition comprising a provided compound (/'. ⁇ ?., the “active ingredient”) into association with a carrier and/or one or more other accessory ingredients, and then, if necessary and/or desirable, shaping and/or packaging the product into a desired single- or multi-dose unit.
  • compositions can be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses.
  • a “unit dose” is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient.
  • the amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and/or a convenient fraction of such a dosage, such as one- half or one-third of such a dosage.
  • Relative amounts of the provided compound, pharmaceutically acceptable excipient, agent, and/or any additional ingredients in a pharmaceutical composition described herein will vary, depending upon the identity, size, and/or condition of the subject diagnosed or treated and further depending upon the route by which the pharmaceutical composition is to be administered.
  • the pharmaceutical composition may comprise between 0.1% and 100% (w/w) agent.
  • compositions used in manufacture of provided pharmaceutical compositions include inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils.
  • Excipients and accessory ingredients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents, may also be present in the pharmaceutical composition.
  • Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, and mixtures thereof.
  • Exemplary granulating and/or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.
  • crospovidone cross-linked poly(vinyl-pyrrolidone)
  • sodium carboxymethyl starch sodium starch glycolate
  • Exemplary surface active agents and/or emulsifiers include natural emulsifiers (e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cellulos
  • Exemplary binding agents include starch (e.g., cornstarch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum®), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and/or mixtures
  • Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, antiprotozoan preservatives, alcohol preservatives, acidic preservatives, and other preservatives.
  • the preservative is an antioxidant.
  • the preservative is a chelating agent.
  • Exemplary antioxidants include alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.
  • Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g. , sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof.
  • EDTA ethylenediaminetetraacetic acid
  • salts and hydrates thereof e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like
  • citric acid and salts and hydrates thereof e.g., citric acid
  • antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.
  • antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.
  • Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.
  • Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.
  • preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant® Plus, Phenonip®, methylparaben, Germall® 115, Germaben® II, NeoIone®, Kathon®, and Euxyl®.
  • Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer
  • Exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.
  • Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea buckt
  • Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof.
  • Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may comprise inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed, groundnut, com, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art such as, for example, water or other solvents,
  • the oral pharmaceutical compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • the conjugates described herein are mixed with solubilizing agents such as Cremophor®, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.
  • sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation can be a sterile injectable solution, suspension, or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that can be employed are water, Ringer’s solution, U.S.P., and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or di-glycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial -retaining filter, or by incorporating sterilizing agents in the form of sterile solid pharmaceutical compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • compositions for rectal or vaginal administration are typically suppositories which can be prepared by mixing the conjugates described herein with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active ingredient is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarding agents such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds, (g) wetting agents such as, for example, cetyl alcohol and glycerol mono
  • Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the art of pharmacology. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • encapsulating compositions which can be used include polymeric substances and waxes.
  • the active ingredient can be in a micro-encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings, and other coatings well known in the pharmaceutical formulating art.
  • the active ingredient can be admixed with at least one inert diluent such as sucrose, lactose, or starch.
  • Such dosage forms may comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms may comprise buffering agents. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • encapsulating agents which can be used include polymeric substances and waxes.
  • Dosage forms for topical and/or transdermal administration of a compound described herein may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and/or patches.
  • the active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier or excipient and/or any needed preservatives and/or buffers as can be required.
  • the present disclosure contemplates the use of transdermal patches, which often have the added advantage of providing controlled delivery of an active ingredient to the body.
  • Such dosage forms can be prepared, for example, by dissolving and/or dispensing the active ingredient in the proper medium.
  • the rate can be controlled by either providing a rate controlling membrane and/or by dispersing the active ingredient in a polymer matrix and/or gel.
  • Formulations suitable for topical administration include, but are not limited to, liquid and/or semi-liquid preparations such as liniments, lotions, oil-in-water and/or water-in-oil emulsions such as creams, ointments, and/or pastes, and/or solutions and/or suspensions.
  • Topically administrable formulations may, for example, comprise from about 1% to about 10% (w/w) active ingredient, although the concentration of the active ingredient can be as high as the solubility limit of the active ingredient in the solvent.
  • Formulations for topical administration may further comprise one or more of the additional ingredients described herein.
  • Suitable devices for use in delivering injectable pharmaceutical compositions described herein include short needle devices.
  • Injectable pharmaceutical compositions can be administered by devices which limit the effective penetration length of a needle into the skin.
  • conventional syringes can be used in the classical mantoux method of administration.
  • Jet injection devices which deliver liquid formulations via a liquid jet injector and/or via a needle.
  • Ballistic powder/particle delivery devices which use compressed gas to accelerate the compound in powder form are suitable.
  • a pharmaceutical composition described herein can be prepared, packaged, and/or sold in a formulation suitable for pulmonary administration via the buccal cavity.
  • a formulation may comprise dry particles which comprise the active ingredient and which have a diameter in the range from about 0.5 to about 7 nanometers, or from about 1 to about 6 nanometers.
  • Such pharmaceutical compositions are conveniently in the form of dry powders for administration using a device comprising a dry powder reservoir to which a stream of propellant can be directed to disperse the powder and/or using a self-propelling solvent/powder dispensing container such as a device comprising the active ingredient dissolved and/or suspended in a low-boiling propellant in a sealed container.
  • Such powders comprise particles wherein at least 98% of the particles by weight have a diameter greater than 0.5 nanometers and at least 95% of the particles by number have a diameter less than 7 nanometers. Alternatively, at least 95% of the particles by weight have a diameter greater than 1 nanometer and at least 90% of the particles by number have a diameter less than 6 nanometers.
  • Dry powder pharmaceutical compositions may include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form.
  • Low boiling propellants generally include liquid propellants having a boiling point of below 65 °F at atmospheric pressure.
  • the propellant may constitute 50 to 99.9% (w/w) of the pharmaceutical composition, and the active ingredient may constitute 0.1 to 20% (w/w) of the pharmaceutical composition.
  • the propellant may further comprise additional ingredients such as a liquid non-ionic and/or solid anionic surfactant and/or a solid diluent (which may have a particle size of the same order as particles comprising the active ingredient).
  • compositions described herein formulated for pulmonary delivery may provide the active ingredient in the form of droplets of a solution and/or suspension.
  • Such formulations can be prepared, packaged, and/or sold as aqueous and/or dilute alcoholic solutions and/or suspensions, optionally sterile, comprising the active ingredient, and may conveniently be administered using any nebulization and/or atomization device.
  • Such formulations may further comprise one or more additional ingredients including a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, and/or a preservative such as methylhydroxybenzoate.
  • the droplets provided by this route of administration may have an average diameter in the range from about 0.1 to about 200 nanometers.
  • Formulations described herein as being useful for pulmonary delivery are useful for intranasal delivery of a pharmaceutical composition described herein.
  • Another formulation suitable for intranasal administration is a coarse powder comprising the active ingredient and having an average particle from about 0.2 to 500 micrometers. Such a formulation is administered by rapid inhalation through the nasal passage from a container of the powder held close to the nares.
  • Formulations for nasal administration may, for example, comprise from about as little as 0.1% (w/w) to as much as 100% (w/w) of the active ingredient, and may comprise one or more of the additional ingredients described herein.
  • a pharmaceutical composition described herein can be prepared, packaged, and/or sold in a formulation for buccal administration.
  • Such formulations may, for example, be in the form of tablets and/or lozenges made using conventional methods, and may contain, for example, 0.1 to 20% (w/w) active ingredient, the balance comprising an orally dissolvable and/or degradable composition and, optionally, one or more of the additional ingredients described herein.
  • formulations for buccal administration may comprise a powder and/or an aerosolized and/or atomized solution and/or suspension comprising the active ingredient.
  • Such powdered, aerosolized, and/or aerosolized formulations when dispersed, may have an average particle and/or droplet size in the range from about 0.1 to about 200 nanometers, and may further comprise one or more of the additional ingredients described herein.
  • a pharmaceutical composition described herein can be prepared, packaged, and/or sold in a formulation for ophthalmic administration.
  • Such formulations may, for example, be in the form of eye drops including, for example, a 0.1- 1.0% (w/w) solution and/or suspension of the active ingredient in an aqueous or oily liquid carrier or excipient.
  • Such drops may further comprise buffering agents, salts, and/or one or more other of the additional ingredients described herein.
  • Other opthalmically-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form and/or in a liposomal preparation. Ear drops and/or eye drops are also contemplated as being within the scope of this disclosure.
  • compositions are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such pharmaceutical compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the pharmaceutical compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with ordinary experimentation. Provided compounds are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the pharmaceutical compositions described herein will be decided by a physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease being diagnosed or treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; the age, body weight, general health, sex, and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.
  • the provided compounds and pharmaceutical compositions provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intraarticular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and/or drops), mucosal, nasal, bucal, sublingual; by intratracheal instillation, bronchial instillation, and/or inhalation; and/or as an oral spray, nasal spray, and/or aerosol.
  • enteral e.g., oral
  • parenteral intravenous, intramuscular, intraarticular, intra-arterial, intramedullary
  • intrathecal subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal
  • topical as by powders, ointments, creams, and/
  • contemplated routes are intraarticular administration, oral administration, intravenous administration (e.g., systemic intravenous injection), regional administration via blood and/or lymph supply, and/or direct administration to an affected site.
  • intraarticular administration e.g., oral administration
  • intravenous administration e.g., systemic intravenous injection
  • regional administration via blood and/or lymph supply e.g., direct administration to an affected site.
  • direct administration e.g., systemic intravenous injection
  • the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract), and/or the condition of the subject (e.g., whether the subject is able to tolerate oral administration).
  • any two doses of the multiple doses include different or substantially the same amounts of an agent described herein.
  • a pharmaceutical composition comprising a provided compound is administered, orally or parenterally, at dosage levels of each pharmaceutical composition sufficient to deliver from about 0.001 mg/kg to about 200 mg/kg in one or more dose administrations for one or several days (depending on the mode of administration).
  • the effective amount per dose varies from about 0.001 mg/kg to about 200 mg/kg, about 0.001 mg/kg to about 100 mg/kg, about 0.01 mg/kg to about 100 mg/kg, from about 0.01 mg/kg to about 50 mg/kg, preferably from about 0.1 mg/kg to about 40 mg/kg, preferably from about 0.5 mg/kg to about 30 mg/kg, from about 0.01 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 10 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic and/or prophylactic effect.
  • the compounds described herein may be at dosage levels sufficient to deliver from about 0.001 mg/kg to about 200 mg/kg, from about 0.001 mg/kg to about 100 mg/kg, from about 0.01 mg/kg to about 100 mg/kg, from about 0.01 mg/kg to about 50 mg/kg, preferably from about 0.1 mg/kg to about 40 mg/kg, preferably from about 0.5 mg/kg to about 30 mg/kg, from about 0.01 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 10 mg/kg, and more preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic and/or prophylactic effect.
  • the desired dosage may be delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks.
  • the desired dosage may be delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations).
  • the pharmaceutical composition described herein is administered at a dose that is below the dose at which the agent causes non-specific effects.
  • the pharmaceutical composition is administered at a dose of about 0.001 mg to about 1000 mg per unit dose. In certain embodiments, the pharmaceutical composition is administered at a dose of about 0.01 mg to about 200 mg per unit dose. In certain embodiments, the pharmaceutical composition is administered at a dose of about 0.01 mg to about 100 mg per unit dose. In certain embodiments, pharmaceutical composition is administered at a dose of about 0.01 mg to about 50 mg per unit dose. In certain embodiments, the pharmaceutical composition is administered at a dose of about 0.01 mg to about 10 mg per unit dose. In certain embodiments, the pharmaceutical composition is administered at a dose of about 0.1 mg to about 10 mg per unit dose.
  • Dose ranges as described herein provide guidance for the administration of provided compounds or pharmaceutical compositions to an adult.
  • the amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult.
  • a dose described herein is a dose to an adult human whose body weight is 70 kg.
  • the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell may be, in non-limiting examples, three doses a day, two doses a day, one dose a day, one dose every other day, one dose every third day, one dose every week, one dose every two weeks, one dose every three weeks, or one dose every four weeks, or even slow dose controlled delivery over a selected period of time using a drug delivery device.
  • the duration between the first dose and last dose of the multiple doses is one day, two days, four days, one week, two weeks, three weeks, one month, two months, three months, four months, six months, nine months, one year, two years, three years, four years, five years, seven years, ten years, fifteen years, twenty years, or the lifetime of the subject, tissue, or cell.
  • the duration between the first dose and last dose of the multiple doses is three months, six months, or one year.
  • the duration between the first dose and last dose of the multiple doses is the lifetime of the subject, tissue, or cell.
  • kits e.g., pharmaceutical packs.
  • the kit comprises a provided compound or pharmaceutical composition described herein, and instructions for using the compound or pharmaceutical composition.
  • the kit comprises a first container, wherein the first container includes the compound or pharmaceutical composition.
  • the kit further comprises a second container.
  • the second container includes an excipient (e.g., an excipient for dilution or suspension of the compound or pharmaceutical composition).
  • the second container includes an additional pharmaceutical agent.
  • the kit further comprises a third container. In certain embodiments, the third container includes an additional pharmaceutical agent.
  • the provided compound or pharmaceutical composition included in the first container and the excipient or additional pharmaceutical agent included in the second container are combined to form one unit dosage form.
  • the provided compound or pharmaceutical composition included in the first container, the excipient included in the second container, and the additional pharmaceutical agent included in the third container are combined to form one unit dosage form.
  • each of the first, second, and third containers is independently a vial, ampule, bottle, syringe, dispenser package, tube, or inhaler.
  • the instructions are for administering the provided compound or pharmaceutical composition to a subject (e.g., a subject in need of diagnosis, treatment, or prevention of a disease described herein). In certain embodiments, the instructions are for contacting a biological sample or cell with the provided compound or pharmaceutical composition. In certain embodiments, the instructions comprise information required by a regulatory agency, such as the U.S. Food and Drug Administration (FDA) or the European Agency for the Evaluation of Medicinal Products (EMA). In certain embodiments, the instructions comprise prescribing information.
  • FDA U.S. Food and Drug Administration
  • EMA European Agency for the Evaluation of Medicinal Products
  • kits and instructions provide for diagnosing a disease in a subject in need thereof. In certain embodiments, the kits and instructions provide for treating a disease in a subject in need thereof. In certain embodiments, the kits and instructions provide for preventing a disease in a subject in need thereof. In certain embodiments, the kits and instructions provide for reducing the risk of developing a disease in a subject in need thereof.
  • a kit described herein may include one or more additional pharmaceutical agents described herein as a separate pharmaceutical composition.
  • the present disclosure also provides methods for diagnosing diseases in a subject in need thereof, the methods comprising administering to the subject an effective amount of a provided compound or pharmaceutical composition.
  • the present disclosure also provides methods for assessing liver function in a subject in need thereof, the methods comprising administering to the subject an effective amount of a provided compound or pharmaceutical composition.
  • the present disclosure also provides methods for assessing biliary obstruction (e.g., within a segment of the liver) in a subject in need thereof, the methods comprising administering to the subject an effective amount of a provided compound or pharmaceutical composition.
  • the biliary obstruction is biliary atresia.
  • the present disclosure also provides methods for assessing bile leak in a subject in need thereof, the methods comprising administering to the subject an effective amount of a provided compound or pharmaceutical composition.
  • the bile leak is a result of injury (e.g., trauma) or surgical procedure (e.g., liver resection, liver transplantation).
  • the method comprises imaging a subject, cell, tissue, or biological sample. In certain embodiments, the method comprises imaging a tissue. In certain embodiments, the method comprises imaging liver tissue. In certain embodiments, the method comprises imaging through positron emission tomography (PET). In certain embodiments, the method comprises imaging through computed tomography (CT). In certain embodiments, the method comprises imaging through PET/CT. In certain embodiments, the imaging comprises detecting a radioisotope. In certain embodiments, the imaging comprises scintillography. In certain embodiments, the imaging comprises detecting radiation from a radioisotope. In certain embodiments, the imaging comprises detecting radiation from a radioisotope-containing compound.
  • PET positron emission tomography
  • CT computed tomography
  • the method comprises imaging through PET/CT.
  • the imaging comprises detecting a radioisotope. In certain embodiments, the imaging comprises scintillography. In certain embodiments, the imaging comprises detecting radiation from a radioisotope. In certain embodiments, the imaging
  • the method comprises imaging a provided compound that degrades less than 10% one hour after preparing the provided compound. In certain embodiments, the method comprises imaging a provided compound that degrades less than 10% two hours after preparing the provided compound. In certain embodiments, the method comprises imaging a provided compound that degrades less than 10% four hours after preparing the provided compound. In certain embodiments, the method comprises imaging a provided compound that degrades less than 10% eight hours after preparing the provided compound. In certain embodiments, the method comprises imaging a provided compound that degrades less than 10% 12 hours after preparing the provided compound. In certain embodiments, the method comprises imaging a provided compound that degrades less than 10% 16 hours after preparing the provided compound. In certain embodiments, the method comprises imaging a provided compound that degrades less than 10% 24 hours after preparing the provided compound.
  • the method for assessing liver function in a subject in need thereof comprises administering to the subject an effective amount of a provided compound and imaging through positron emission tomography (PET).
  • the provided compound is labeled with 18 F.
  • the method for assessing biliary obstruction (e.g., within a segment of the liver) in a subject in need thereof comprises administering to the subject an effective amount of a provided compound and imaging through positron emission tomography (PET).
  • PET positron emission tomography
  • the provided compound is labeled with 18 F.
  • the biliary obstruction is biliary atresia.
  • the method for assessing bile leak in a subject in need thereof comprises administering to the subject an effective amount of a provided compound and imaging through positron emission tomography (PET).
  • the provided compound is labeled with 18 F.
  • the bile leak is a result of injury (e.g., trauma) or surgical procedure (e.g., liver resection, liver transplantation).
  • the present disclosure also provides methods for treating diseases in a subject in need thereof, the methods comprising administering to the subject an effective amount of a provided compound or pharmaceutical composition.
  • the present disclosure also provides methods for preventing diseases in a subject in need thereof, the methods comprising administering to the subject an effective amount of a provided compound or pharmaceutical composition.
  • the compounds and pharmaceutical compositions provided herein being useful as described herein may be at least in part due to the localization to liver cancer cells by the compounds and pharmaceutical compositions provided herein.
  • the compounds and pharmaceutical compositions provided herein may increase the potency and/or efficacy in diagnosing, treating, and/or preventing liver cancer in a subject, cell, tissue, or biological sample.
  • the compounds and pharmaceutical compositions provided herein may increase bioavailability, safety, and/or therapeutic window, reduce toxicity and/or resistance, and/or increase subject compliance, in a subject.
  • the present disclosure also provides methods for inhibiting cell proliferation or promoting apoptosis in a subject in need thereof or in a cell, tissue, or biological sample, comprising administering to the subject or contacting the cell, tissue, or biological sample with an effective amount of a provided compound or pharmaceutical composition, wherein the cell, tissue, or biological sample is in vivo.
  • the present disclosure also provides methods for inhibiting cell proliferation or promoting apoptosis in a cell, tissue, or biological sample, comprising contacting the cell, tissue, or biological sample with an effective amount of a provided compound or pharmaceutical composition, wherein the cell, tissue, or biological sample is in vitro.
  • the present disclosure also provides methods for imaging a subject, comprising administering to the subject an effective amount of a provided compound or pharmaceutical composition, and detecting a radioisotope.
  • the method comprises imaging a tissue.
  • the method comprises imaging liver tissue.
  • the method comprises imaging through positron emission tomography (PET).
  • PET positron emission tomography
  • CT computed tomography
  • the method comprises imaging through PET/CT.
  • the imaging comprises detecting a radioisotope.
  • the imaging comprises scintillography.
  • the imaging comprises detecting radiation from a radioisotope.
  • the imaging comprises detecting radiation from a radioisotope-containing compound. In certain embodiments, the method comprises imaging a provided compound that degrades less than 10% one hour after preparing the provided compound. In certain embodiments, the method comprises imaging a provided compound that degrades less than 10% two hours after preparing the provided compound.
  • the cell, tissue, or biological sample is present in vitro. In certain embodiments, the cell, tissue, or biological sample is present in vivo. In certain embodiments, the cell, tissue, or biological sample is present ex vivo. In certain embodiments, the cell is a cancer cell. In certain embodiments, the cell is a liver cancer cell. In certain embodiments, the cell is a hepatocellular carcinoma (HCC) cell. In certain embodiments, the tissue is liver tissue. In certain embodiments, the tissue is cancerous liver tissue. In certain embodiments, the tissue is liver tissue containing cancer cells. In certain embodiments, the tissue is liver tissue containing liver cancer cells. In certain embodiments, the tissue is liver tissue containing HCC cells. In certain embodiments, the method further comprises administering to the subject one or more additional pharmaceutical agents and/or radiation. In certain embodiments, the method further comprises contacting the cell, tissue, or biological sample with one or more additional pharmaceutical agents and/or radiation.
  • HCC hepatocellular carcinoma
  • the subject has not been administered one or more additional pharmaceutical agents, surgery, radiation therapy, transplantation (e.g., stem cell transplantation, bone marrow transplantation), immunotherapy, and/or chemotherapy.
  • the subject has been administered one or more additional pharmaceutical agents, surgery, radiation therapy, transplantation (e.g., stem cell transplantation, bone marrow transplantation), immunotherapy, and/or chemotherapy.
  • the subject is resistant to one or more additional pharmaceutical agents, surgery, radiation therapy, transplantation (e.g., stem cell transplantation, bone marrow transplantation), immunotherapy, and/or chemotherapy.
  • the subject has been administered one or more additional pharmaceutical agents, surgery, radiation therapy, transplantation (e.g., stem cell transplantation, bone marrow transplantation), immunotherapy, and/or chemotherapy, and has previously experienced a remission.
  • the subject is immunocompromised.
  • the subject has been diagnosed with liver cancer.
  • the subject has been diagnosed with hepatocellular carcinoma (HCC).
  • HCC hepatocellular carcinoma
  • the subject suffers from underlying liver disease, chronic hepatitis, and/or cirrhosis.
  • the subject has not been diagnosed with liver cancer.
  • the subject has not been diagnosed with hepatocellular carcinoma (HCC).
  • the subject does not suffer from underlying liver disease, chronic hepatitis, and/or cirrhosis.
  • the subject is a human.
  • the subject is a human aged 18 years or older.
  • the subject is a human aged younger than 18 years.
  • the disease is a cancer.
  • the cancer is a liver cancer.
  • the cancer is a hepatocellular carcinoma (HCC).
  • the compound is detected in an organ or tissue within 15 minutes of administration, within 30 minutes of administration, within 45 minutes of administration, within 1 hour of administration, within 2 hours of administration, within 3 hours of administration, or within 4 hours of administration.
  • the compound is detected in the cecum within 15 minutes of administration, within 30 minutes of administration, within 45 minutes of administration, within 1 hour of administration, within 2 hours of administration, within 3 hours of administration, or within 4 hours of administration.
  • the compound is detected in the gallbladder within 15 minutes of administration, within 30 minutes of administration, within 45 minutes of administration, within 1 hour of administration, within 2 hours of administration, within 3 hours of administration, or within 4 hours of administration.
  • the compound is detected in the large intestine within 15 minutes of administration, within 30 minutes of administration, within 45 minutes of administration, within 1 hour of administration, within 2 hours of administration, within 3 hours of administration, or within 4 hours of administration. In certain embodiments, the compound is detected in the liver within 15 minutes of administration, within 30 minutes of administration, within 45 minutes of administration, within 1 hour of administration, within 2 hours of administration, within 3 hours of administration, or within 4 hours of administration. In certain embodiments, the compound is detected in the liver within 15 minutes of administration. In certain embodiments, the compound is detected in the liver within 30 minutes of administration. In certain embodiments, the compound is detected in the liver within 45 minutes of administration. In certain embodiments, the compound is detected in the liver within 1 hour of administration.
  • the compound is detected in the liver within 2 hours of administration. In certain embodiments, the compound is detected in the liver within 3 hours of administration. In certain embodiments, the compound is detected in the liver within 4 hours of administration. In certain embodiments, the compound is detected in the small intestine within 15 minutes of administration, within 30 minutes of administration, within 45 minutes of administration, within 1 hour of administration, within 2 hours of administration, within 3 hours of administration, or within 4 hours of administration. In certain embodiments, the compound is detected in the spleen within 15 minutes of administration, within 30 minutes of administration, within 45 minutes of administration, within 1 hour of administration, within 2 hours of administration, within 3 hours of administration, or within 4 hours of administration.
  • the compound is not detected in an organ or tissue 15 minutes after administration, 30 minutes after administration, 45 minutes after administration, 1 hour after administration, 2 hours after administration, 3 hours after administration, or 4 hours after administration.
  • the compound is not detected in the heart 15 minutes after administration, 30 minutes after administration, 45 minutes after administration, 1 hour after administration, 2 hours after administration, 3 hours after administration, or 4 hours after administration.
  • the compound is not detected in the lungs 15 minutes after administration, 30 minutes after administration, 45 minutes after administration, 1 hour after administration, 2 hours after administration, 3 hours after administration, or 4 hours after administration.
  • the activity concentration in an organ or tissue after administration is at least 5, at least 10, at least 15, at least 20, or at least 25.
  • the activity concentration in the cecum after administration is at least 5, at least 10, at least 15, at least 20, or at least 25.
  • the activity concentration in the gallbladder after administration is at least 5, at least 10, at least 15, at least 20, or at least 25.
  • the activity concentration in the large intestine after administration is at least 5, at least 10, at least 15, at least 20, or at least 25.
  • the activity concentration in the liver after administration is at least 5, at least 10, at least 15, at least 20, or at least 25.
  • the activity concentration in the liver after administration is at least 5.
  • the activity concentration in the liver after administration is at least 10. In certain embodiments, the activity concentration in the liver after administration is at least 15. In certain embodiments, the activity concentration in the liver after administration is at least 20. In certain embodiments, the activity concentration in the liver after administration is at least 25. In certain embodiments, the activity concentration in the small intestine after administration is at least 5, at least 10, at least 15, at least 20, or at least 25. In certain embodiments, the activity concentration in the spleen after administration is at least 5, at least 10, at least 15, at least 20, or at least 25. In certain embodiments, the activity concentration is measured by standardized uptake value (SUV).
  • SUV standardized uptake value
  • the activity uptake in an organ or tissue after administration is at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99%.
  • the activity uptake in the cecum after administration is at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99%.
  • the activity uptake in the gallbladder after administration is at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99%.
  • the activity uptake in the large intestine after administration is at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99%.
  • the activity uptake in the liver after administration is at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99%.
  • the activity uptake in the liver after administration is at least about 5%. In certain embodiments, the activity uptake in the liver after administration is at least about 10%. In certain embodiments, the activity uptake in the liver after administration is at least about 15%. In certain embodiments, the activity uptake in the liver after administration is at least about 20%. In certain embodiments, the activity uptake in the liver after administration is at least about 25%. In certain embodiments, the activity uptake in the liver after administration is at least about 30%. In certain embodiments, the activity uptake in the liver after administration is at least about 35%. In certain embodiments, the activity uptake in the liver after administration is at least about 40%. In certain embodiments, the activity uptake in the liver after administration is at least about 45%.
  • the activity uptake in the liver after administration is at least about 50%. In certain embodiments, the activity uptake in the liver after administration is at least about 55%. In certain embodiments, the activity uptake in the liver after administration is at least about 60%. In certain embodiments, the activity uptake in the liver after administration is at least about 65%. In certain embodiments, the activity uptake in the liver after administration is at least about 70%. In certain embodiments, the activity uptake in the liver after administration is at least about 75%. In certain embodiments, the activity uptake in the liver after administration is at least about 80%. In certain embodiments, the activity uptake in the liver after administration is at least about 85%. In certain embodiments, the activity uptake in the liver after administration is at least about 90%.
  • the activity uptake in the liver after administration is at least about 95%. In certain embodiments, the activity uptake in the liver after administration is at least about 98%. In certain embodiments, the activity uptake in the liver after administration is at least about 99%. In certain embodiments, the activity uptake in the small intestine after administration is at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about
  • the activity uptake in the spleen after administration is at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99%.
  • the activity uptake in an organ or tissue after administration is a range between a percentage described in this paragraph and another percentage described in this paragraph, inclusive.
  • the activity uptake after administration is measured by percentage injected dose (%ID).
  • the present disclosure also provides a provided compound or pharmaceutical composition for use in diagnosing a disease in a subject in need thereof.
  • the present disclosure also provides a provided compound or pharmaceutical composition for use in treating a disease in a subject in need thereof.
  • the present disclosure also provides a provided compound or pharmaceutical composition for use in preventing a disease in a subject in need thereof.
  • the present disclosure also provides a provided compound or pharmaceutical composition for the manufacture of a medicament for diagnosis of a disease in a subject in need thereof.
  • the present disclosure also provides a provided compound or pharmaceutical composition for the manufacture of a medicament for treatment of a disease in a subject in need thereof.
  • the present disclosure also provides a provided compound or pharmaceutical composition for the manufacture of a medicament for prevention of a disease in a subject in need thereof.
  • in vitro methods provided herein can be carried out, e.g., in an assay, cell culture, or biological sample.
  • the cell is obtained from an organism, such as a subject.
  • the cell is a liver cancer cell.
  • the cell is a hepatocellular carcinoma (HCC) cell.
  • the methods further comprise measuring or assessing the level of one or more properties of the cell.
  • the level of one or more properties of the cell is assessed following contacting the cell with any of the compounds or pharmaceutical compositions described herein.
  • the level of one or more properties following contacting the cell with any of the compounds or pharmaceutical compositions described herein is compared to the level of one or more properties in a reference sample or prior to contacting the cell with the compounds or pharmaceutical composition.
  • the contacting the cell with any of the compounds or pharmaceutical compositions described herein increases one or more properties of the cell.
  • the methods described herein may be used to determine whether a cell is susceptible to diagnosis or treatment with the compounds or pharmaceutical compositions described herein.
  • the cell is determined to be susceptible to diagnosis or treatment with the compound or pharmaceutical composition. In some embodiments, if the level of one or more properties is increased following contacting the cell with any of the compounds or pharmaceutical compositions described herein, the compound or pharmaceutical composition is determined to be a candidate for a disease associated with the cell.
  • the present disclosure provides methods of preparing compounds of Formula I-g-i: stereoisomer, or prodrug thereof, the method comprising reacting an amine of Formula I-f-ii: or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or prodrug thereof, with a compound of Formula II: pb2 cw R
  • each occurrence of R 2 is independently hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • R bl is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, and contains at least one radioisotope;
  • R b2 is halogen or -OR A ;
  • R A is independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  • the compound of Formula II is an activated ester of Formula Il-a or Formula Il-b: or salt thereof
  • the method further comprises converting an ester of Formula II-c:
  • the method comprises reacting the ester of Formula II-c: o ⁇ z ORA
  • the method comprises reacting a compound of Formula Il-d:
  • the leaving group is NMes.
  • reacting the compound of Formula ILd with 18F“ comprises adding [ 18 F]KF/K222. In certain embodiments, reacting the compound of Formula ILd with 18F comprises adding [ 18 F]TBAF.
  • the present disclosure provides methods of preparing compounds of Formula Lj-i: zNH
  • R 4 (Lj-i), or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or prodrug thereof the method comprising reacting an amine of Formula Lf-ii: or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or prodrug thereof, with a compound of formula: or salt thereof, wherein: each occurrence of R 2 is independently hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and n is 1, 2, 3, 4, 5,
  • Fibrolamellar carcinoma is a primary liver cancer that most commonly arises in healthy adolescents and young adults in a background of normal liver tissue 1-3 .
  • FLC hepatocellular carcinoma
  • Theranostic approaches to various cancers have made significant progress in recent years.
  • This approach combines an agent to diagnose or localize disease and a related agent to treat the disease 7 by taking advantage of radioisotopes of various elements with specific properties in regards to their particle and energy emission- determining their applicability for diagnostic imaging (positron emission tomography (PET), magnetic resonance imaging (MRI)) or therapeutic cytotoxicity.
  • diagnostic imaging positron emission tomography (PET), magnetic resonance imaging (MRI)
  • Current theranostic pairs used in clinical practice include agents for imaging and treatment of thyroid cancer, neuroblastoma, pheochromocytoma, hepatocellular carcinoma, prostate cancer, and neuroendocrine tumors.
  • the approach for thyroid cancer is based on the sodium/iodide symporter, which is present on thyroid cancer cells and results in the uptake of 123 I for diagnostic imaging and 131 I for therapy.
  • l 23 I/ 131 1-labclcd metaiodobenzylguanidine (mIBG), an analogue of norepinephrine is transported through norepinephrine channels into tumor cells.
  • mIBG l 23 I/ 131 1-labclcd metaiodobenzylguanidine
  • lutetium 177 conjugated to a human prostate-specific membrane antigen-targeting ligand 177 Lu-PSMA-617) was approved by the Food and Drug Administration (FDA) for treatment of prostate cancer.
  • FDA Food and Drug Administration
  • the currently approved theranostic pair for hepatocellular carcinoma uses " m Tc-macroaggregates of human serum albumin as a diagnostic agent and 90 Y microspheres as therapeutic agent.
  • This radioembolization approach uses interventional techniques to deliver glass 90 Y microspheres directly into the feeding vessels of the tumor and due to the size of the microspheres they become lodged in the tumor.
  • This is a mechanical approach as opposed to a molecular approach and therefore only applicable if the arterial supply of the tumor is suitable which may not be the case for many metastatic lesions. 11 Therefore development of molecular-based liver cancer- specific theranostic agents are desirable.
  • ICG indocyanine green
  • ICG serum levels have been used as a surrogate for liver function. 15
  • this property is used for identification of tumor nodules during surgery.
  • several groups have confirmed the utility of ICG for identification of primary liver and metastatic HCCs 16-21 . It is also demonstrated that ICG also accumulates in FLC (FIGs. 31A-31D).
  • ICG is administered several days prior to surgery, which subsequently is cleared from the blood and normal liver but is retained in tumor tissue.
  • a near-infrared camera is used to identify ICG retaining tumor tissue since it fluoresces in response to nearinfrared wave.
  • ICG organic anion transporting polypeptides
  • SCOIBI organic anion transporting polypeptides
  • SLCO2B1 solute transporters are normally responsible for uptake of bile salts by hepatocytes from plasma.
  • MDR3 belongs to the ATP-binding cassette transporters, which are expressed on the canalicular membranes of hepatocytes and transport solutes from hepatocytes into the bile. Tumor cells also express MDR3, however, liver cancer cells do not form bile canaliculi, and therefore ICG is retained in the tumor tissue. 28
  • ICG intracranial pressure
  • Surgical experience in 2 patients with FLC demonstrated ICG uptake by tumor tissue in the liver as well as metastatic deposits (FIGs. 31A-31D).
  • Analysis of RNA-seq data demonstrates that two of the known ICG uptake transporters are also expressed in FLC. Even though the expression is lower in tumor tissue compared to normal liver tissue, it is likely sufficient for uptake as demonstrated through clinical observation (FIGs. 31A-31D).
  • the MDR3 transporter which is responsible for export of ICG into the bile canaliculi is also expressed in tumor cells, albeit at lower levels.
  • these two cancers share similar expression levels of ICG transporters SLCO1B1 and SLCO2B1 which suggests that they may have comparable properties for ICG retention.
  • 18 F was selected as the initial radioisotope given that 1) it is the radioisotope used clinically in 18 F-fluorodeoxyglucose (FDG) PET and PET/CT imaging, 2) it is safe and tolerable and 3) its properties are amenable for conjugation to ICG.
  • FDG PET is a widely used modality and is based on cellular uptake of glucose and therefore cancers with a high rate of glucose uptake demonstrate a more intense signal on PET imaging.
  • 31-33 As a detectable radionuclide on PET scan, 64 Cu has gained tremendous attention in recent years partly due to: 1) its longer halflife compared to 18 F and 2) the pairing with a therapeutic 67 Cu-based compound as a theranostic modality.
  • [ 18 F]ICG was administrated to wild-type mice and dynamic PET/CT images were obtained during the first hour (FIGs. 26A-26D) followed by a static image at 4 hours (FIGS. 3OA-3D).
  • [ 18 F]ICG is cleared from the circulation and localized to the liver under similar kinetics as ICG itself. As illustrated in FIGs. 26A-26D, at time 0, the tracer is localized to the heart and the major vessels and by 5 minutes, the tracer is predominantly localized to the liver. This rapid clearance of [ 18 F]ICG from the serum and concentration in the liver is in line with the known 4-5 minute serum half-life of ICG 14 . There is no significant uptake by any other organs via the circulation.
  • FIG. 18B illustrates the percentage of injected dose (% ID) of [ 18 F]ICG in several organs of interest. Nearly 70% of [ 18 F]ICG is localized to the liver by 10 minutes and by 4 hours about 40% ID is localized to the liver.
  • Xenotransplantation of the following cell lines is performed: FLX1 (FLC), Huh-7 (HCC) and HepG2 (well-differentiated HCC) in immunodeficient mice. Since the ability of Huh-7 and HepG2 cells lines to uptake ICG has been previously demonstrated in mouse models 34 , these cell line xenograft models provide an efficient approach to assess uptake of [ 18 F]ICG and [ 64 Cu]ICG.
  • Huh-7 and HepG2 cell lines are important in demonstrating the ability of [ 18 F]ICG and [ 64 Cu]ICG to localize to metastatic liver tumors.
  • they are transferred to LFIC for subcutaneous injection (5xl0 6 cells/mouse in 1:1 v:v with 50pL Matrigel) and establishment of xenograft models.
  • LFIC subcutaneous injection
  • the development process for these models is established, demonstrating ICG uptake by Huh7 tumor cells at 0.5 mg/kg ICG dose which is 10-20 fold lower than previously reported animal dosing (FIG. 32). Therefore, the dose is escalated to an appropriate level.
  • NRAS G12v /shP53 induced orthotopic HCC model is used. 35 This model is created via hyperdynamic tail vein injection of NRAS G12v /shP53 plasmids in 8-week old mice resulting in intrahepatic tumor development after 2 months.
  • ICG conjugates localize to tumor cells and 2) the duration of ICG retention within the tumor. Developing a precise understanding of ICG retention in the tumor bed facilitates the determination of dosing frequency for therapeutic agents. Since synthesis of ICG-radionuclide conjugates is more labor intensive and costly, tumor localization of ICG conjugates is initially assessed using ‘cold’ reference compounds.
  • the reference compounds are synthesized by conjugating ICG to non-emitting isotopes (e.g. fluorine- 19 instead of fluorine- 18).
  • the cold ICG-conjugate has the same chemical structure as the radionuclide conjugate and therefore it is expected to have similar pharmacokinetics.
  • the minimal dose of the reference ICG compounds that localizes to the tumor is determined by injecting the tumorbearing mice with ICG-conjugates at 2, 5, and 10 mg/kg followed by in vivo fluorescence imaging at the following intervals post-injection: 1 hour, 4 hours, 1 day, 3 days, 5 days, and 7 days.
  • the timeline and dosing are based on previously published results. 34,36 If there is significant tumor signal at 7 days, the imaging is extended until the time at which there is complete signal dissipation from the tumor.
  • the dose range for each cold ICG-conjugate is determined, which guides the dosing of ‘hot’ ICG-radionuclide in subsequent experiments.
  • [ 18 F]ICG has been synthesized with purity > 95%.
  • the tumor-bearing mice undergo intravenous injection with [ 18 F]ICG and imaging under the following schedule: 1) dynamic PET/CT imaging for 1 hour; and 2) static imaging at 4 hours following injection. This schedule is designed based on the 110-minute half-life of 18 F. Dosing is determined by data obtained using the cold reference compound, [ 19 F]ICG.
  • the compound [ 64 Cu]ICG has also been synthesized. Given the 12.7 hour half-life of 64 Cu, imaging can be performed at a later time point following injection compared to [ 18 F]ICG. For [ 64 Cu]ICG imaging in tumor-bearing mice, the following imaging schedule is used: 1) dynamic PET/CT imaging for 1 hour after injection; and 2) static imaging at 24 and 48 hours. The ability to perform the imaging beyond 24-48 hours provides the necessary time for [ ⁇ CuJICG to be completely cleared from the liver, thereby increasing the signal to background ratio of [ ⁇ CuJICG retaining nodules within the liver. Dosing is determined by data obtained using cold reference compound.
  • NRAS G12v /shP53 induced HCC mice undergo imaging following [ 18 F]ICG and [ ⁇ CuJICG administration using the above-mentioned respective imaging protocols.
  • 67 Cu Measure the anti-tumor activity of [ 67 Cu]ICG.
  • cytotoxic radionuclides which are used for cancer therapeutics as conjugates to antibodies and small molecules.
  • 67 Cu is selected since it is a short-range beta-emitting nuclide and has gained significant attention in recent years due to its favorable properties for nuclear medicine applications as well as improvements in its production.
  • 37,38 67 Cu has a mean energy of 141 keV, similar to the energy of 131 I (180 keV), a widely used radionuclide.
  • Advantages of 67 Cu over 131 I is the lower gamma radiation associated with 67 Cu, thereby delivering a lower whole -body dose to the patient as well as the clinical personnel. 38
  • [ 64 Cu]ICG and [ 67 Cu]ICG as a theranostic pair of agents has advantages in clinical practice as they provide a pair of agents, which complement each other as diagnostic and radiotherapeutic agents with similar mechanisms of action.
  • SUV standardized uptake value
  • Another experimental group undergoes injection with only [ 67 Cu]ICG, without initial imaging with [ ⁇ CujlCG.
  • In vivo fluorescence imaging is used to confirm localization of ICG-radionuclide conjugates to tumors.
  • Tumor volume (mm 3 ) is measured and recorded every 3 days for 15 days to generate a tumor growth curve for each animal. The mice are monitored for any adverse effects during this time.
  • the serum levels of AST, ALT, GGT, and bilirubin are also measured as biochemical markers for liver injury.
  • the mice undergo MRI to assess tumor size.
  • PET/CT with [ ⁇ CujlCG is performed to assess SUV at tumor site and compared to baseline SUV at the start of the treatment.
  • mice subsequently undergo euthanasia on day 15 and the tumor and liver tissue are removed for histologic analysis.
  • the tumor and liver sections are examined to assess tumor cell viability as well as evidence of acute liver injury.
  • the tumor sections are also examined for the localization of ICG or [ 67 Cu]ICG (cytoplasmic vs. extracellular) using near-infrared confocal microscopy. This data demonstrate whether there are any differences between ICG and [ 67 Cu]ICG efflux from the tumor cells as well as a quantitative measure of residual ICG in the tumor bed.
  • the data obtained from the first series of experiments are used to guide the effect size of [ 67 Cu]ICG on tumor tissue. If the tumor effect size is not large, the following experimental conditions can be adjusted in order to achieve a larger effect size: 1) Thirty-day duration of treatment +/- additional [ 67 Cu]ICG dose on day 15; and 2) administer [ 67 Cu]ICG dose at higher doses for 15-day treatment. The results of these experiments are then used to guide further adjustments to obtain optimal treatment effect.
  • [ 18 F]FEA was prepared by fluorination of the tosyl precursor and distillation into the reaction vessel containing MeCN (300 pL). Precursor (0.32 mg) in MeCN (800 pL) was added. Aliquots of the crude mixture were analysed over time with increasing temperature. Two radiopeaks believed to correspond to [ 18 F]ICG-A and [ 18 F]ICG-B were obtained. At 90 °C 40% conversion from [ 18 F]FEA was obtained. The initial results for the formation of [ 18 F]ICG-A/B were promising, with stability and reactivity of the precursor up to at least 90°C tested. Conversions obtained are suitable for in vivo imaging, and a radiolabelling process for the ICG derivative allows for imaging in vivo.
  • 64 Cu or 67 Cu are complexed to ICG-NOTA.
  • HC1 is mixed with ammonium acetate buffer and ICG-NOTA.
  • the resulting mixture (pH 4) is placed on an agitating mixer and shaken at 300 rpm for 30 min at room temperature.
  • the solution is diluted with water and passed through a Sep-Pak C18 Plus Light cartridge (rinsed with EtOH first, then with H2O before use).
  • the cartridge is rinsed with water, then with 10% MeOH in water , then eluted with MeOH.
  • Flow direction used for the elution is opposite to the flow direction used for trapping crude material and rinsing.
  • the eluate is evaporated to dryness at 60 °C under nitrogen flow and the residue is redissolved in 0.9% saline.
  • the molar activity of the chelation complex solution used for the biodistribution studies and imaging experiments is 3 MBq/nmol.
  • the modalities were whole body PET/CT and whole blood gamma counting which were performed on the mice using the imaging agent 18 F-SFB-ICG as outlined in Table 1. Briefly, the mice were imaged in a 2-bed imaging hotel with imaging agent administered intravenously while animals were on camera (volume dosed was maintained constant to keep mass dose constant). 1 hour dynamic PET data was acquired, followed by CT. A static 30 minute PET dataset was acquired at 4 hours, also followed by CT. A blood sample was taken immediately following each imaging time point for gamma counting.
  • PET/CT PET images were co-registered to CT images and resampled to uniform voxel size (0.2 mm 3 ).
  • the injected activity doses were normalized to the averaged activity in the field of view (FOV) in the final 6 frames of the dynamic scan (FOV-based normalization).
  • FOV field of view
  • Regions of Interest were defined using various methods in VivoQuant software: A fixed volume ellipsoidal ROI was placed in the center of the heart, to encompass a volume of representative concentration for that region. The fixed volume sphere ROIs were placed in the center of the lobes of the lungs (2), and throughout the spleen (3) to encompass a volume of representative concentration for those regions. Based on the CT and PET, the following organs were segmented as completely as possible: liver, gallbladder, small intestines, cecum, and large intestines. The activity concentration was reported as Standardized Uptake Value (SUV), equating to the percentage injected dose per gram of tissue (%ID/g) normalized to subject body weight. For fully segmented organs, uptake was also reported in percentage injected dose (%ID). Figures 17A-17D show resulting PET/CT images of a representative wild type mouse.
  • SUV Standardized Uptake Value
  • articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context.
  • Embodiments or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context.
  • the disclosure includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process.
  • the disclosure includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.
  • the disclosure encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim.
  • any claim that is dependent on another claim can be modified to include one or more limitations found in any other claims that is dependent on the same base claim.
  • elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the disclosure, or aspects of the disclosure, is/are referred to as comprising particular elements and/or features, certain embodiments of the disclosure or aspects of the disclosure consist, or consist essentially of, such elements and/or features.

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Abstract

La présente divulgation concerne des composés de formule I et F, qui sont des dérivés du vert d'indocyanine (ICG), et des sels, solvates, hydrates, polymorphes, co-cristaux, tautomères, stéréoisomères et promédicaments pharmaceutiquement acceptables de ceux-ci. La présente divulgation concerne également des compositions pharmaceutiques et des kits comprenant les composés, ou des sels, solvates, hydrates, polymorphes, co-cristaux, tautomères, stéréoisomères ou promédicaments pharmaceutiquement acceptables de ceux-ci, et des méthodes de diagnostic, de traitement ou de prévention de maladies par administration à un sujet dont l'état le nécessite, des composés, ou des sels, solvates, hydrates, polymorphes, co-cristaux, tautomères, stéréoisomères ou promédicaments pharmaceutiquement acceptables de ceux-ci, ou des compositions pharmaceutiques de ceux-ci. La présente divulgation concerne en outre des méthodes de préparation de composés de formule I et F.
PCT/US2023/026034 2022-06-23 2023-06-23 Modification de vert d'indocyanine (icg) pour le traitement du cancer du foie WO2023250116A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140275526A1 (en) * 2013-03-15 2014-09-18 University Of Massachusetts Sulfonate compounds
CN108264475A (zh) * 2016-12-30 2018-07-10 中国科学院深圳先进技术研究院 吲哚菁绿衍生物及制备方法
US20180346728A1 (en) * 2015-12-01 2018-12-06 Dishman Pharmaceuticals And Chemicals Limited Process for the preparation of indocyanine green

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140275526A1 (en) * 2013-03-15 2014-09-18 University Of Massachusetts Sulfonate compounds
US20180346728A1 (en) * 2015-12-01 2018-12-06 Dishman Pharmaceuticals And Chemicals Limited Process for the preparation of indocyanine green
CN108264475A (zh) * 2016-12-30 2018-07-10 中国科学院深圳先进技术研究院 吲哚菁绿衍生物及制备方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
JO GAYOUNG, LEE BO YOUNG, KIM EUN JEONG, PARK MIN HO, HYUN HOON: "Indocyanine Green and Methyl-β-Cyclodextrin Complex for Enhanced Photothermal Cancer Therapy", BIOMEDICINES, vol. 8, no. 11, 5 November 2020 (2020-11-05), pages 476, XP055969000, DOI: 10.3390/biomedicines8110476 *

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